bluuebunny/crossref_metadata_2025 huggingface dataset:
The protein product of the proto-oncogene c-cbl forms a complex with phosphatidylinositol 3-kinase p85 and CD19 in anti-IgM-stimulated human B-lymphoma cells
Authors: Beckwith M , Jorgensen G , Longo DL
Published: October 2019

Multiple signal transduction cascades, consisting of multiple interacting proteins, are activated following stimulation through most cell surface receptors, including the immunoglobulin receptor of B lymphocytes. In this report, we investigated the multimolecular complexes formed following anti-Ig stimulation of a human B-lymphoma cell line, resulting in activation of phosphatidylinositol 3-kinase (PI3K). PI3K is a lipid kinase that consists of an 85-kD regulatory subunit, bound to a 110-kD catalytic subunit. CD19 is a 95-kD B-cell surface marker that contains a consensus binding motif for PI3Kp85 in the cytoplasmic domain and recruits PI3K activity in activated B cells. The protein product of the c-cbl protooncogene is a 120-kD protein that is expressed in early B-lineage cells and in myeloid cells and is phosphorylated on tyrosine following receptor-mediated signaling in T and B lymphocytes. We demonstrate here that phosphorylated c-cbl complexes with CD19 and with PI3Kp85 via its C-terminal SH2 domain, and that both c-cbl and CD19 are associated with active PI3K in anti-Ig-stimulated cells. Although we cannot differentiate between a three-component, c-cbl/CD19/p85 complex and individual two-component complexes, these studies suggest that c-cbl may function as a docking protein, possibly linking distinct signal transduction pathways.
Heterogeneity of the human CD4+ T-cell population: two distinct CD4+ T- cell subsets characterized by coexpression of CD45RA and CD45RO isoforms
Authors: Hamann D , Baars PA , Hooibrink B , van Lier RW
Published: October 2019

Activation of unprimed CD4+CD45RA+/RO- T-cells results in a gradual loss of CD45RA expression concomitant with the acquisition of CD45RO. It has been suggested that this conversion occurs in vivo through a CD45RAbright/RObright stage. Next to this small CD45RAbright/RObright subset (Dbright), a larger subpopulation that expresses both RA and RO isoforms at low levels (Ddull) can be found in the circulating CD4+ T-cell population of all donors. The properties of the latter population are largely undefined. Here, we show that Ddull cells have an intermediate phenotype for antigens such as CD31, CD621, CD58, and CD95 that are differentially expressed on unprimed versus primed T cells. In addition, they are able to provide help for B-cell differentiation and contain substantial numbers of tetanus toxoid (TT)-specific precursor cells. Remarkably, both intracellular cytokine staining and analysis of T-cell clones showed that Ddull cells and CD45RO+ T-cells produce comparable high amounts of both interferon (IFN)-gamma and interleukin (IL)-4, which clearly distinguishes them from CD45RA+ and Dbright T-cells. Finally, prolonged culture of sorted Ddull cells in a mixture of IL-2, IL-6, and tumor necrosis factor (TNF)-alpha showed that about half of the population retained the Ddull phenotype. Part of the cells upregulated the CD45RA isoform, whereas only a minority switched to single CD45RO expression. Our findings indicate that the Ddull population contains primed T cells, some of which may reacquire an “unprimed” phenotype in the absence of antigenic stimulation.
Functional role of cation-independent mannose 6-phosphate/insulin-like growth factor II receptor in cell adhesion and proliferation of a human myeloma cell line OPM-2
Authors: Nishiura T , Karasuno T , Yoshida H , Nakao H , Ogawa M , Horikawa Y , Yoshimura M , Okajima Y , Kanakura Y , Kanayama Y , Matsuzawa Y
Published: October 2019

The molecular mechanism underlying the interaction between myeloma cells and stromal cells was investigated by using a human myeloma cell line (OPM-2) and human umbilical vein endothelial cells (HUVECs). Adhesion of OPM-2 cells to HUVECs was found to be significantly augmented with treatment of OPM-2 cells with an alpha-glycosidase inhibitor, castanospermine (CSP). The treatment of OPM-2 cells with CSP resulted in alteration of oligosaccharide structures of cell surface glycoproteins particularly at molecular weight of 220 kD (GP220). To determine if GP220 was involved in the adhesion of OPM-2 cells to HUVECs, cell surface glycoproteins of HUVECs were labeled by biotin and were incubated with the PVDF membrane to which cell surface glycoproteins of OPM-2 cells were blotted. The biotinylated glycoproteins at the plasma membrane of HUVECs specifically bound to GP220 of OPM-2 cells. Purification and partial amino acid sequencing of GP220 revealed that GP220 had a structure homologous to cation-independent mannose 6-phosphate/insulin-like growth factor-II (CIM6P/IGF-II) receptor. Furthermore, an antibody against CIM6P/IGF-II receptor was reactive with GP220, indicating that GP220 was a CIM6P/IGF-II receptor. The adhesion of OPM-2 cells to HUVECs was inhibited by mannose 6-phosphate. Moreover, M6P was found to suppress the adhesion of human myeloma cell lines, OPM-2 and RPMI 8226, to bone marrow stromal cells that was established from the patients with multiple myeloma. In addition, proliferation of OPM-2 was stimulated in response to IGF-II. These results suggest that CIM6P/IGF-II receptor may be functional in terms of supporting cell adhesion and proliferation of myeloma cells.
Restoration of the CCAAT Box or Insertion of the CACCC Motif Activate δ-Globin Gene Expression
Authors: Tang Delia C. , Ebb David , Hardison Ross C. , Rodgers Griffin P.
Published: October 2019

Hemoglobin A2 (HbA2 ), which contains δ-globin as its non–α-globin, represents a minor fraction of the Hb found in normal adults. It has been shown recently that HbA2 is as potent as HbF in inhibiting intracellular deoxy-HbS polymerization, and its expression is therefore relevant to sickle cell disease treatment strategies. To elucidate the mechanisms responsible for the low-level expression of the δ-globin gene in adult erythroid cells, we first compared promoter sequences and found that the δ-globin gene differs from the β-globin gene in the absence of an erythroid Krüppel-like factor (EKLF ) binding site, the alteration of the CCAAT box to CCAAC, and the presence of a GATA-1 binding site. Second, serial deletions of the human δ-globin promoter sequence fused to a luciferase (LUC) reporter gene were transfected into K562 cells. We identified both positive and negative regulatory regions in the 5′ flanking sequence. Furthermore, a plasmid containing a single base pair (bp) mutation in the CCAAC box of the δ promoter, restoring the CCAAT box, caused a 5.6-fold and 2.4-fold (P < .05) increase of LUC activity in transfected K562 cells and MEL cells, respectively, in comparison to the wild-type δ promoter. A set of substitutions that create an EKLF binding site centered at −85 bp increased the expression by 26.8-fold and 6.5-fold (P < .05) in K562 and MEL cells, respectively. These results clearly demonstrate that the restoration of either an EKLF binding site or the CCAAT box can increase δ-globin gene expression, with potential future clinical benefit.
Correlation of Bcl-2 Rearrangement With Clinical Characteristics and Outcome in Indolent Follicular Lymphoma
Authors: López-Guillermo Armando , Cabanillas Fernando , McDonnell Timothy I. , McLaughlin Peter , Smith Terry , Pugh William , Hagemeister Fredrick , Rodrı́guez M. Alma , Romaguera Jorge E. , Younes Anas , Sarris Andreas H. , Preti H. Alejandro , Lee Ming-Seng
Published: October 2019

The t(14;18) translocation, which involves the bcl-2oncogene, occurs in follicular lymphomas (FL) at two common sites: the major breakpoint region (MBR) and the minor cluster region (mcr). The biological and clinical significance of these breakpoints is unknown. The bcl-2 breakpoint site was determined in 247 previously untreated patients (49% men; median age 52 years) with indolent FL (155 grade I, 83 grade II, and 8 grade III) to correlate it with pretreatment characteristics, response, and outcome. The bcl-2 breakpoint site was determined by a polymerase chain reaction method of peripheral blood (all cases), bone marrows (149 cases), and fresh lymph node biopsy specimens (68 cases). The breakpoint site occurred at MBR in 175 cases (71%) and atmcr in 27 (11%). In 45 cases (18%), no breakpoint was detected (germline). No significant relationship was found between the rearrangements and the expression of BLC-2 and BAXproteins. Patients’ germline for MBR and mcr tended to present more frequently with stage IV disease and higher β2-microglobulin (β2M) levels, whereas mcr-rearranged patients presented more frequently with early stage and normal β2M. The complete response rate of germline patients was significantly lower than that of MBR and mcr patients. An estimated 3-year failure-free survival (FFS) for mcr, MBR, and germline cases was 95%, 76%, and 57%, respectively (P < .001). Thebcl-2 breakpoint site was independent of serum β2M and lactate dehydrogenase in its correlation with FFS. In conclusion, thebcl-2 rearrangement site is an important prognostic factor in indolent FL, useful to identify patients who may require different treatment.
Aging, hematopoiesis, and the myelodysplastic syndromes
Authors: Chung Stephen S. , Park Christopher Y.
Published: October 2019

The aging hematopoietic system undergoes numerous changes, including reduced production of red blood cells and lymphocytes as well as a relative increase in the production of myeloid cells. Emerging evidence indicates that many of these changes are due to selection pressures from cell-intrinsic and cell-extrinsic factors that result in clonal shifts in the hematopoietic stem cell (HSC) pool, resulting in predominant HSC clones that exhibit the functional characteristics associated with HSC aging. Given the recent descriptions of clonal hematopoiesis in aged populations, the increased risk of developing hematologic malignancies in individuals with clonal hematopoiesis, and the many similarities in hematopoietic aging and acquired bone marrow failure (BMF) syndromes, such as myelodysplastic syndromes (MDS), this raises significant questions regarding the relationship between aging hematopoiesis and MDS, including the factors that regulate HSC aging, whether clonal hematopoiesis is required for the development of MDS, and even whether BMF is an inevitable consequence of aging. In this article, we will review our current understanding of these processes and the potential intersections among them.
Hemophilia gene therapy comes of age
Authors: George Lindsey A.
Published: October 2019

Concurrent with the development of recombinant factor replacement products, the characterization of the F9 and F8 genes over 3 decades ago allowed for the development of recombinant factor products and made the hemophilias a target disease for gene transfer. The progress of hemophilia gene therapy has been announced in 3 American Society of Hematology scientific plenary sessions, including the first “cure” in a large animal model of hemophilia B in 1998, first in human sustained vector-derived factor IX activity in 2011, and our clinical trial results reporting sustained vector-derived factor IX activity well into the mild or normal range in 2016. This progression to clinically meaningful success combined with numerous ongoing recombinant adeno-associated virus (rAAV)–mediated hemophilia gene transfer clinical trials suggest that the goal of gene therapy to alter the paradigm of hemophilia care may soon be realized. Although several novel therapeutics have recently emerged for hemophilia, gene therapy is unique in its potential for a one-time disease-altering, or even curative, treatment. This review will focus on the prior progress and current clinical trial investigation of rAAV-mediated gene transfer for hemophilia A and B.
Cord blood transplantation recapitulates fetal ontogeny with a distinct molecular signature that supports CD4+ T-cell reconstitution
Authors: Hiwarkar Prashant , Hubank Mike , Qasim Waseem , Chiesa Robert , Gilmour Kimberly C. , Saudemont Aurore , Amrolia Persis J. , Veys Paul
Published: October 2019

Key Points

Cord blood T cells are ontogenetically distinct from the peripheral blood T cells. Recapitulation of fetal ontogeny after cord blood transplantation results in rapid CD4+ T-cell reconstitution.
TFPIα interacts with FVa and FXa to inhibit prothrombinase during the initiation of coagulation
Authors: Wood Jeremy P. , Petersen Helle H. , Yu Bingke , Wu Xiaoai , Hilden Ida , Mast Alan E.
Published: October 2019

Key Points

TFPIα inhibits prothrombinase through interactions with the FXa active site and B-domain acidic region and heavy chain of FXa-activated FVa. Leu252-Thr255 of the TFPIα basic region is necessary for inhibitory activity but not for binding the FXa-activated FVa acidic region.
Sociodemographic factors in patients continuing warfarin vs those transitioning to direct oral anticoagulants
Authors: Schaefer Jordan K. , Sood Suman L. , Haymart Brian , Gu Xiaokui , Kong Xiaowen , Kline-Rogers Eva , Almany Steven , Kozlowski Jay , Krol Gregory D. , Kaatz Scott , Froehlich James B. , Barnes Geoffrey D.
Published: October 2019

Key Points

Race, income, and partnered status were associated with anticoagulant use but clinical factors had a stronger association.
Silencing of HDAC6 as a therapeutic target in chronic lymphocytic leukemia
Authors: Maharaj Kamira , Powers John J. , Achille Alex , Deng Susan , Fonseca Renee , Pabon-Saldana Mibel , Quayle Steven N. , Jones Simon S. , Villagra Alejandro , Sotomayor Eduardo M. , Sahakian Eva , Pinilla-Ibarz Javier
Published: October 2019

Although the treatment paradigm for chronic lymphocytic leukemia (CLL) is rapidly changing, the disease remains incurable, except with allogeneic bone marrow transplantation, and resistance, relapsed disease, and partial responses persist as significant challenges. Recent studies have uncovered roles for epigenetic modification in the regulation of mechanisms contributing to malignant progression of CLL B cells. However, the extent to which epigenetic modifiers can be targeted for therapeutic benefit in CLL patients remains poorly explored. We report for the first time that expression of epigenetic modifier histone deacetylase 6 (HDAC6) is upregulated in CLL patient samples, cell lines, and euTCL1 transgenic mouse models compared with HDAC6 in normal controls. Genetic silencing of HDAC6 conferred survival benefit in euTCL1 mice. Administration of isoform-specific HDAC6 inhibitor ACY738 in the euTCL1 aging and adoptive transfer models deterred proliferation of CLL B cells, delayed disease onset via disruption of B-cell receptor signaling, and sensitized CLL B cells to apoptosis. Furthermore, coadministration of ACY738 and ibrutinib displayed synergistic cell kill against CLL cell lines and improved overall survival compared with either single agent in vivo. These results demonstrate for the first time the therapeutic efficacy of selective HDAC6 inhibition in preclinical CLL models and suggest a rationale for the clinical development of HDAC6 inhibitors for CLL treatment, either alone or in combination with Bruton tyrosine kinase inhibition.
Stem cell safe harbor: the hematopoietic stem cell niche in zebrafish
Authors: Wattrus Samuel J. , Zon Leonard I.
Published: October 2019

Each stem cell resides in a highly specialized anatomic location known as the niche that protects and regulates stem cell function. The importance of the niche in hematopoiesis has long been appreciated in transplantation, but without methods to observe activity in vivo, the components and mechanisms of the hematopoietic niche have remained incompletely understood. Zebrafish have emerged over the past few decades as an answer to this. Use of zebrafish to study the hematopoietic niche has enabled discovery of novel cell–cell interactions, as well as chemical and genetic regulators of hematopoietic stem cells. Mastery of niche components may improve therapeutic efforts to direct differentiation of hematopoietic stem cells from pluripotent cells, sustain stem cells in culture, or improve stem cell transplant.
Two-Dimensional Hole-Array Grating-Coupling-Based Excitation of Bloch Surface Waves for Highly Sensitive Biosensing
Authors: Ge Daohan , Shi Jianpei , Rezk Ahmed , Ma Chao , Zhang Liqiang , Yang Ping , Zhu Shining
Published: October 2019

In this study, a surface diffraction two-dimensional (2D) grating structure was placed on the topmost layer of distributed Bragg reflectors (DBRs) for biosensing. Bloch surface wave (BSW) resonance was realized by coupling a 2D subwavelength hole-array grating and could be excited at different locations: the surface of 2D-grating layer or the inter-face between the DBR and bio-solution. Material losses in the multilayer dielectric were measured to test the robustness of this scheme. Both the surface diffraction-grating BSW (DG-BSW) and the alternative guided grating-coupled BSW (GC-BSW) configuration showed markedly enhanced angular sensitivity compared to conventional prism-coupled schematics. Exciting these modes using a grating-coupling technique appears to yield different extreme sensitivity modes with a maximum of 1190°/RIU for DG-BSW and 2255°/RIU for GC-BSW. Refractive index sensors with a high figure of merit may be realized via such compact configurations.
Point-of-care ultrasound defines gastric content in elective surgical patients with type 2 diabetes mellitus: a prospective cohort study
Authors: Zhou Li , Yang Yi , Yang Lei , Cao Wei , Jing Heng , Xu Yan , Jiang Xiaojuan , Xu Danfeng , Xiao Qianhui , Jiang Chunling , Bo Lulong
Published: October 2019

Background

Delayed gastric emptying and the resultant “full stomach” is the most important risk factor for perioperative pulmonary aspiration. Using point-of-care gastric sonography, we aimed to investigate the prevalence of full stomach and its risk factors in elective surgical patients with type 2 diabetes.

Methods

Type 2 diabetic and non-diabetic elective surgical patients were included from July 2017 to April 2018 in a 1:1 ratio. The study was retrospectively registered at July 2017, after enrollment of the first participant. Gastric ultrasound was performed 2 h after ingesting clear fluid or 6 h after a light meal. Full stomach was defined by the presence of gastric content in both semi-recumbent and right lateral decubitus positions. For patients with full or intermediate stomach, consecutive ultrasound scan was performed until empty stomach was detected. Logistic regression analyses were used to identify risk factors associated with full stomach.

Results

Fifty-two type 2 diabetic and fifty non-diabetic patients were analyzed. The prevalence of full stomach was 48.1% (25/52) in diabetic patients, with 44.0% for 2-h fast after clear fluid and 51.9% for 6-h fast after a light meal, significantly higher than 8% (4/50) in non-diabetic patients (P = 0.000). The average time to empty stomach in diabetic patients was 146.50 ± 40.91 mins for clear liquid and 426.50 ± 45.25 mins for light meal, respectively. Further analysis indicated that presence of diabetes-related eye disease was an independent risk factor of full stomach in diabetic patients (OR = 4.83, P = 0.010).

Conclusions

Almost half of type 2 diabetic patients have a full stomach following the current preoperative fasting guideline. Preoperative ultrasound assessment of gastric content in type 2 diabetic patients is suggested, especially for those with diabetes -related eye disease.

Trial registration

The trial was registered at www.clinicaltrials.gov with registration number NCT03217630. Retrospectively registered on 14th July 2017.
Going beyond classic echo in aortic stenosis: left atrial mechanics, a new marker of severity
Authors: Marques-Alves Patrícia , Marinho Ana Vera , Teixeira Rogério , Baptista Rui , Castro Graça , Martins Rui , Gonçalves Lino
Published: October 2019

Background

There is limited information regarding left atrial (LA) mechanics in aortic valve stenosis (AS). We assessed LA mechanics in AS through speckle-tracking echocardiography (STE) according to severity and prognosis.

Methods

We included 102 patients diagnosed with severe AS (sAS) and 80 patients with moderate AS (mAS), all with preserved ejection fraction and no coronary artery disease. LA mechanics and left ventricular global longitudinal strain (LV-GLS) were assessed by STE. The cohort was followed-up for a median of 30 (IQR 12.6–50) months, and outcomes were determined (combined outcome of HF, death, and aortic valve replacement).

Results

In our sample set, values of LV-GLS (− 18.5% vs − 17.1, p = 0.025), E/e’ ratio (15.8 vs 18.4, p = 0.03), and global LA mechanics (LA ɛsys, 23% vs 13.8%, p < 0.001) were worse for sAS compared to those for mAS. However, LA ɛsys (AUC 0.85, 95% CI 0.78–0.90, p < 0.001), ɛe (AUC 0.83, 95% CI 0.75–0.88, p < 0.001), and ɛa (AUC 0.80, 95% CI 0.70–0.84, p < 0.001) were the best discriminators of sAS, with sensitivities higher than 85%. LA ɛsys showed a stronger correlation with both aortic valve area (r2 = 0.6, p < 0.001) and mean LV/aortic gradient (r2 = 0.55, p < 0.001) than LV-GLS (r2 = 0.3 and r2 = 0.25, p = 0.01). Either LV-GLS or LA ɛsys, but not the E/e’ ratio, TAPSE, or RV/RA gradient, were a significant predictors of the combined outcome.

Conclusions

LA global strain was the best discriminator of severity, surpassing E/e’ ratio and LV-GLS, and a significant predictor of prognosis in AS.
Circ-SMARCA5 suppresses progression of multiple myeloma by targeting miR-767-5p
Authors: Liu Haiyan , Wu Yan , Wang Shunye , Jiang Jie , Zhang Chenlu , Jiang Yijing , Wang Xingfeng , Hong Lewen , Huang Hongming
Published: October 2019

Background

We aimed to investigate the correlation of Circ-SMARCA5 with disease severity and prognosis in multiple myeloma (MM), and its underlying mechanisms in regulating cell proliferation and apoptosis.

Methods

Bone marrow samples from 105 MM patients and 36 healthy controls were collected for Circ-SMARCA5 expression measurement. And the correlation of Circ-SMARCA5 expression with patients’ characteristics and survival was determined. In vitro, the effect of Circ-SMARCA5 on MM cell proliferation and apoptosis was evaluated by altering Circ-SMARCA5 expression through transfection. Rescue experiments and luciferase assay were further performed to explore the mechanism of Circ-SMARCA5 as well as its potential target miR-767-5p in regulating MM cell activity.

Results

Circ-AMARCA5 was downregulated in MM and presented a good value in distinguishing MM patients from controls and it was also negatively correlated with Beta-2-microglobulin (β2-MG) level and International Staging System (ISS) stage. Additionally, Circ-SMARCA5 high expression was associated with higher CR as well as better PFS and OS. As for in vitro experiments, Circ-SMARCA5 expression was lower in MM cell lines compared with normal cells, and Circ-SMARCA5 overexpression inhibited cell proliferation but promoted cell apoptosis in RPMI8226 cells. Rescue experiments disclosed that the effect of Circ-SMARCA5 on cell activity was attenuated by miR-767-5p, and luciferase reporter assay revealed direct binding between Circ-SMARCA5 and miR-767-5p.

Conclusions

Circ-SMARCA5 is downregulated and correlated with lower β2-MG level and ISS stage as well as better prognosis in MM patients, and it inhibits proliferation but promotes apoptosis of MM cells via directly sponging miR-767-5p.
Bifocal osteosynthesis to treat radial shortening deformity with dislocation of the inferior radioulnar joint
Authors: Guan Junjie , Ruan Hongjiang , Yin Jimin , Chai Yimin , Kang Qinglin
Published: October 2019

Background

Several methods have been reported to correct deformity and shortening of the distal radius. However, the results are not entirely satisfactory. The results of bifocal osteosynthesis were retrospectively analyzed in this study.

Methods

Eight patients treated with bifocal osteosynthesis were evaluated retrospectively. Pre-operative and post-operative clinical and radiographic examinations were performed. Subjective symptoms and objective joint function were assessed. Radiographic data of the extent of radial lengthening and distal radial articular angle were collected.

Results

The mean follow-up period was 46 months (37–68 months). Satisfactory wrist appearance and radial lengthening was achieved in all patients. All patients were satisfied with the wrist appearance and willing to undergo the same treatment again. The range of motion (ROM) of the forearm and wrist was significantly improved. Pin-track infections occurred in two patients, for which they received wound care and oral antibiotics. Complications such as fixation device failure, tendon rupture, fracture of regenerated bone or nerve impairment did not occur. The duration of lengthening depended on the shortening of the radius. Delayed union in the docking site was observed in two patients and union was achieved after bone grafting.

Conclusions

Bifocal osteosynthesis using the Ilizarov method provides a useful method for correction of radial shortening deformity with dislocation of the inferior radioulnar joint. Despite the fact that we did not validate pre-and post-operation functional outcome scores, all patients were satisfied with the wrist appearance and function.
Recovering the capability to work among patients with chronic low Back pain after a four-week, multidisciplinary biopsychosocial rehabilitation program: 18-month follow-up study
Authors: Ibrahim Maha E. , Weber Kerstin , Courvoisier Delphine S. , Genevay Stéphane
Published: October 2019

Background

Chronic low back pain (LBP) is a leading cause of disability worldwide. Biopsychosocial rehabilitation programs have been advocated for its management, especially since the widespread acceptance of the biopsychosocial model of chronic pain. Despite extensive evidence of its short-term benefits, few studies have reported on its long-term effect and more specifically on indirect outcomes such as return to work and quality of life (QoL). The present study evaluated the long-term effect of a multidisciplinary biopsychosocial rehabilitation (MBR) program for patients with chronic LBP, for which short- and intermediate-term efficacy had been established, with an emphasis on recovering work capability.

Methods

This prospective cohort study enrolled 201 patients on a four-week MBR program incorporating physical and occupational therapies and psychological counselling. Assessments occurred at program admission and discharge and at 6 and 18 months. Work capability, Oswestry Disability Index, Tampa Scale for Kinesiophobia, Core Outcome Measures Index (COMI), and Hospital Anxiety and Depression Scale were assessed. Multiple mixed models were used to detect changes in each outcome. Logistic regressions were calculated to identify predictors of recovery of work capability.

Results

Of the 201 patients who fulfilled the eligibility criteria, 160 (79.8%) attended the discharge assessment, 127 (63.2%) attended the 6-month follow-up, and 107 (53.3%) continued to the 18-month follow-up. Initially, 128 patients (71.5%) had been on sick leave. At 6 and 18 months, 72 (56.7%) and 84 (78.5%) participants had recovered their work capability, respectively. There were significant improvements in pain, disability, kinesiophobia, and anxiety and depression scores over time. Patients who recovered work capability showed significantly greater improvements in their total COMI score, general QoL, and disability, which were the best three predictors of recovering work capability.

Conclusions

This study extends previous results confirming the program’s contribution to recovering work capability among chronic LBP patients.
Metabolic perturbations in mutants of glucose transporters and their applications in metabolite production in Escherichia coli
Authors: Jung Hwi-Min , Im Dae-Kyun , Lim Jae Hyung , Jung Gyoo Yeol , Oh Min-Kyu
Published: October 2019

Background

Most microorganisms have evolved to maximize growth rate, with rapid consumption of carbon sources from the surroundings. However, fast growing phenotypes usually feature secretion of organic compounds. For example, E. coli mainly produced acetate in fast growing condition such as glucose rich and aerobic condition, which is troublesome for metabolic engineering because acetate causes acidification of surroundings, growth inhibition and decline of production yield. The overflow metabolism can be alleviated by reducing glucose uptake rate.

Results

As glucose transporters or their subunits were knocked out in E. coli, the growth and glucose uptake rates decreased and biomass yield was improved. Alteration of intracellular metabolism caused by the mutations was investigated with transcriptome analysis and 13C metabolic flux analysis (13C MFA). Various transcriptional and metabolic perturbations were identified in the sugar transporter mutants. Transcription of genes related to glycolysis, chemotaxis, and flagella synthesis was downregulated, and that of gluconeogenesis, Krebs cycle, alternative transporters, quorum sensing, and stress induced proteins was upregulated in the sugar transporter mutants. The specific production yields of value-added compounds (enhanced green fluorescent protein, γ-aminobutyrate, lycopene) were improved significantly in the sugar transporter mutants.

Conclusions

The elimination of sugar transporter resulted in alteration of global gene expression and redirection of carbon flux distribution, which was purposed to increase energy yield and recycle carbon sources. When the pathways for several valuable compounds were introduced to mutant strains, specific yield of them were highly improved. These results showed that controlling the sugar uptake rate is a good strategy for ameliorating metabolite production.
Efficacy of insecticides used in indoor residual spraying for malaria control: an experimental trial on various surfaces in a “test house”
Authors: Corrêa Ana Paula S. A. , Galardo Allan K. R. , Lima Luana A. , Câmara Daniel C. P. , Müller Josiane N. , Barroso Jéssica Fernanda S. , Lapouble Oscar M. M. , Rodovalho Cynara M. , Ribeiro Kaio Augusto N. , Lima José Bento P.
Published: October 2019

Background

Malaria is a public health problem in the Brazilian Amazon region. In integrated vector management for malaria (anopheline) control, indoor residual spraying (IRS) represents one of the main tools in the basic strategy applied in the Amazonian states. It is essential to understand the residual efficacy of insecticides on different surfaces to determine spray cycles, ensure their rational use, and prevent wastage. This study aimed to evaluate the residual efficacy of six insecticide formulations used in the National Malaria Control Programme on four different types of walls in a field simulation at a “test house”.

Methods

The tests were performed as a field-simulating evaluation at a “test house” built in the municipality of Macapá. Six insecticide formulations comprising four pyrethroids, a carbamate, and an organophosphate were used, and evaluated when applied on different wall surfaces: painted wood, unpainted wood, plastered cement, and unplastered cement. The insecticides were applied to the interior walls of the “test house” by a trained technician.

Results

In the bioassays performed with pyrethroids, deltamethrin water-dispersible granules (WG) performed particularly well, presenting residual bioefficacy of 8 months on both wood surfaces after the IRS, whereas alpha-cypermethrin suspension concentrate (SC) and etofenprox wettable powder (WP) demonstrated residual bioefficacy of 4 months on at least one of the wood surfaces; however, the pyrethroid lambda-cyhalothrin WP showed a low residual bioefficacy (< 3 months) on all tested surfaces, demonstrating its inefficiency for areas with a long transmission cycle of malaria. For the carbamate-bendiocarb WP, residual bioefficacy for 3 months was achieved only on wood surfaces. In general, the organophosphate pirimifos-methyl capsule suspension (CS) demonstrated the best result, with a mortality rate < 80% over a period of 6 months on all surfaces tested.

Conclusion

Insecticide efficiency varies among different types of surface; therefore, a “test house” is a valuable evaluation tool. This work highlights the usefulness of associating the residual efficacy of insecticides on the surfaces commonly found in houses in endemic areas, together with knowledge about the transmission cycle duration of the transmission cycle and the insecticide susceptibility of the vector. This association helps in the decision-making for the malaria control intervention regarding.
Construction of biocompatible bovine serum albumin nanoparticles composed of nano graphene oxide and AIEgen for dual-mode phototherapy bacteriostatic and bacterial tracking
Authors: Zhang Yongxin , Fu Hao , Liu De-E , An Jinxia , Gao Hui
Published: October 2019

Background

Efficient and highly controllable antibacterial effect, as well as good biocompatibility are required for antibacterial materials to overcome multi-drug resistance in bacteria. Herein, nano graphene oxide (NGO)-based near-infrared (NIR) photothermal antibacterial materials was schemed to complex with biocompatible bovine serum albumin (BSA) and aggregation-induced emission fluorogen (AIEgen) with daylight-stimulated ROS-producing property for dual-mode phototherapy in the treatment of antibiotic resistance bacteria.

Results

Upon co-irradiation of daylight and NIR laser, NGO-BSA-AIE nanoparticles (NPs) showed superiorly antibacterial effect (more than 99%) both against amoxicillin (AMO)-resistant Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) by comparison with sing-model phototherapy. Meanwhile, the NGO-BSA-AIE NPs displayed prominent stability and excellently controllable biocompatibility. More importantly, under daylight irradiation, the AIEgen not only produced plentiful ROS for killing bacteria, but also presented fluorescence image for tracking bacteria.

Conclusions

Hence, the designed system provided tempting strategy of employing light as impetus for tracking bacterial distribution and photothermal/photodynamic synergistic treatment of antibiotic resistance antibacterial.
Computer algorithm can match physicians’ decisions about blood transfusions
Authors: Yao Yuanyuan , Cifuentes Jenny , Zheng Bin , Yan Min
Published: October 2019

Background

Checking appropriateness of blood transfusion for quality assurance required enormous usage of time and human resources from the healthcare system. We report here a new machine learning algorithm for checking blood transfusion quality.

Materials and methods

The multilayer perceptron neural network (MLPNN) was designed to learn an expert’s judgement from 4946 clinical cases. The accuracy in predicting the blood transfusion was then reported.

Results

We achieved a 96.8% overall accuracy rate, with a 99% match rate to the experts’ judgement on those appropriate cases and 90.9% on the inappropriate cases.

Conclusions

Machine learning algorithm can accurately match to human judgement by feeding in pre-surgical information and key laboratory variables.
Spatially resolved transcriptomics reveals plant host responses to pathogens
Authors: Giolai Michael , Verweij Walter , Lister Ashleigh , Heavens Darren , Macaulay Iain , Clark Matthew D.
Published: October 2019

Background

Thorough understanding of complex model systems requires the characterisation of processes in different cell types of an organism. This can be achieved with high-throughput spatial transcriptomics at a large scale. However, for plant model systems this is still challenging as suitable transcriptomics methods are sparsely available. Here we present GaST-seq (Grid-assisted, Spatial Transcriptome sequencing), an easy to adopt, micro-scale spatial-transcriptomics workflow that allows to study expression profiles across small areas of plant tissue at a fraction of the cost of existing sequencing-based methods.

Results

We compare the GaST-seq method with widely used library preparation methods (Illumina TruSeq). In spatial experiments we show that the GaST-seq method is sensitive enough to identify expression differences across a plant organ. We further assess the spatial transcriptome response of Arabidopsis thaliana leaves exposed to the bacterial molecule flagellin-22, and show that with eukaryotic (Albugo laibachii) infection both host and pathogen spatial transcriptomes are obtained.

Conclusion

We show that our method can be used to identify known, rapidly flagellin-22 elicited genes, plant immune response pathways to bacterial attack and spatial expression patterns of genes associated with these pathways.
Social group and health care provider interventions to increase the demand for malaria rapid diagnostic test among community members in Ebonyi state, Nigeria: study protocol for a cluster randomized controlled trial
Authors: Omale Ugwu I. , Azuogu Benedict N. , Alo Chihurumnanya , Madubueze Ugochukwu C. , Oka Onyinyechukwu U. , Okeke Kingsley C. , Okafor Ifeyinwa M. , Utulu Rowland , Akpan Uduak E. , Iloke Chijioke V. , Nnubia Anthonia O. , Eze Ifeyinwa I. , Anene Ogechukwu C. , Nnabu Chukwuka R. , Ibemesi Deborah C.
Published: October 2019

Background

The World Health Organization recommended (in 2010) universal testing for suspected malaria, due to some fundamental changes in malaria trends such as the declining incidence of malaria in high-burden countries, the emergence of parasite resistance to anti-malarial drugs especially artemisinin-based combination therapies (ACTs) and the increased availability of diagnostic testing such as the malaria rapid diagnostic test (MRDT). The Nigerian government has long adopted this recommendation and with the support of foreign partners has scaled up the availability of MRDT. However, the malaria/MRDT rate in the communities is still far short of the recommendation. This study aims to evaluate the effectiveness of social group and social group/provider interventions in increasing the demand (use and/or request) for MRDT among community members with fever or malaria-like illness in Ebonyi state, Nigeria.

Methods

A three-arm, parallel, stratified cluster randomized design will be used to evaluate the effect of two interventions compared to control: control involves the usual practice of provision of MRDT services by public primary healthcare providers and patent medicine vendors; social group intervention involves the sensitization/education of social groups about MRDT; social group/provider intervention involves social group treatment plus the training of healthcare providers in health communication about MRDT with clients. The primary outcome is the proportion of children under 5 years of age with fever/malaria-like illness, in the 2 weeks preceding a household survey, who received MRDT. The co-primary outcome is the proportion of children ages 5 years and above and adults (excluding pregnant women) with fever/malaria-like illness, in the 2 weeks preceding a household survey, who received MRDT. The primary outcome will be assessed through household surveys at baseline and at the end of the study.

Discussion

The pragmatic and behavioural nature of the interventions delivered to groups of individuals and the need to minimize contamination informed the use of a cluster-randomized design in this study in investigating whether the social group and social group/provider interventions will increase the demand for MRDT among community members. “Pragmatic” means the interventions would occur in natural settings or real- life situations.

Trial registration

ISRCTN, ISRCTN14046444. Registered on 14 August 2018.
Nanostructured lipid carriers of ivermectin as a novel drug delivery system in hydatidosis
Authors: Ahmadpour Ehsan , Godrati-Azar Zahra , Spotin Adel , Norouzi Roghayeh , Hamishehkar Hamed , Nami Sanam , Heydarian Peyman , Rajabi Saba , Mohammadi Maryam , Perez-Cordon Gregorio
Published: October 2019

Background

The larval stage of the tapeworm Echinococcus granulosus is the causative agent of hydatid disease in humans. This zoonotic parasitic infection remains a major health problem in certain areas of the world where is still endemic. In view of the ineffectiveness of some drug treatments, the surgical removal of cysts remains the preferred treatment option together with the administration of albendazole and mebendazole. However, severe side effects of these drugs have been reported which demands developing new scolicidal agents that confer suitable efficacy and fewer side effects during surgery.

Methods

To that purpose, in the present work we assessed the effectiveness of ivermectin (IVM), a macrocyclic lactone endectocide that has shown to be an effective nematocidal drug against other important parasitic infections. To overcome the limitations observed in some drug formulations and resistance, we used nano lipid carriers (NLCs) as a targeted and sustained drug delivery system for IVM. We evaluated the in vitro cestocidal and apoptotic effects of NLCs-loaded IVM versus IVM by quantifying the expression of caspase-3 mRNA.

Results

We found that after 60 and 120 min of administration, 800 μg/ml and 400 μg/ml NLCs-loaded IVM induced 100% mortality, respectively. On the other hand, the 800 μg/ml of IVM induced 100% mortality rate 150 min after administration. Additionally, we found that NLCs-loaded IVM induced higher mRNA caspase-3 expression suggesting a more potent apoptotic effect on the parasite.

Conclusions

These data suggest that NLCs-loaded IVM may be a promising alternative to current treatments although in vivo studies are needed.
Association between metabolic syndrome and the incidence of gastric cancer: a meta-analysis of cohort studies
Authors: Li Zhibin , Han Hongfeng , Chang Yuan
Published: October 2019

Background

Previous studies investigating the association between metabolic syndrome (MetS) and incidence of gastric cancer (GC) showed inconsistent results. The aim of the study was to evaluate the influence of MetS on GC risk in a meta-analysis.

Methods

Cohort studies that evaluating the association between MetS and GC were identified via systematic search of PubMed, Embase, Web of Science, and Scopus databases. Pooled analyses were performed via a random-effect model or a fixed effect model according to the heterogeneity among the studies. Predefined subgroup analyses were performed to evaluate whether gender or ethnic group of the patients affected the results.

Results

Overall, eight cohort studies with 8,745,671 participants were included, and 37,245 GC cases occurred during follow-up. Results showed that MetS defined by the revised National Cholesterol Education Program’s Adults Treatment Panel III criteria was not associated with a significantly affected GC risk (adjusted risk ratio [RR]: 1.03, p = 0.59; I2 = 79%). Subgroup analyses showed that MetS was not associated with a significantly affected risk of GC in male or female patients, and in Asians or Caucasians. Moreover, meta-analysis of four datasets showed that MetS defined by the International Diabetes Federation criteria was also not associated with a significant affected risk of GC (adjusted RR: 0.80, p = 0.05; I2 = 0%).

Conclusions

These results indicated that current evidence from epidemiological studies does not support that patients with MetS are at higher risk for the development of GC.
Brain STAT5 Modulates Long-Term Metabolic and Epigenetic Changes Induced by Pregnancy and Lactation in Female Mice
Authors: Teixeira Pryscila D S , Ramos-Lobo Angela M , Furigo Isadora C , Donato Jose
Published: October 2019

Several metabolic and behavioral adaptations that emerge during pregnancy remain present after weaning. Thus, reproductive experience causes long-lasting metabolic programming, particularly in the brain. However, the isolate effects of pregnancy or lactation and the molecular mechanisms involved in these long-term modifications are currently unknown. In the current study, we investigated the role of brain signal transducer and activator of transcription-5 (STAT5), a key transcription factor recruited by hormones highly secreted during gestation or lactation, for the long-term adaptations induced by reproductive experience. In control mice, pregnancy followed by lactation led to increased body adiposity and reduced ambulatory activity later in life. Additionally, pregnancy+lactation induced long-term epigenetic modifications in the brain: we observed upregulation in hypothalamic expression of histone deacetylases and reduced numbers of neurons with histone H3 acetylation in the paraventricular, arcuate, and ventromedial nuclei. Remarkably, brain-specific STAT5 ablation prevented all metabolic and epigenetic changes observed in reproductively experienced control female mice. Nonetheless, brain-specific STAT5 knockout (KO) mice that had the experience of pregnancy but did not lactate showed increased body weight and reduced energy expenditure later in life, whereas pregnancy KO and pregnancy+lactation KO mice exhibited improved insulin sensitivity compared with virgin KO mice. In summary, lactation is necessary for the long-lasting metabolic effects observed in reproductively experienced female mice. In addition, epigenetic mechanisms involving histone acetylation in neuronal populations related to energy balance regulation are possibly associated with these long-term consequences. Finally, our findings highlighted the key role played by brain STAT5 signaling for the chronic metabolic and epigenetic changes induced by pregnancy and lactation.
Games and the Art of Agency
Authors: Nguyen C. Thi
Published: October 2019

Games may seem like a waste of time, where we struggle under artificial rules for arbitrary goals. The author suggests that the rules and goals of games are not arbitrary at all. They are a way of specifying particular modes of agency. This is what make games a distinctive art form. Game designers designate goals and abilities for the player; they shape the agential skeleton which the player will inhabit during the game. Game designers work in the medium of agency. Game-playing, then, illuminates a distinctive human capacity. We can take on ends temporarily for the sake of the experience of pursuing them. Game play shows that our agency is significantly more modular and more fluid than we might have thought. It also demonstrates our capacity to take on an inverted motivational structure. Sometimes we can take on an end for the sake of the activity of pursuing that end.
Work-related risk factors for Carpal Tunnel Syndrome among Majmaah University female touchscreen users
Authors: Kashoo Faizan Zaffar
Published: October 2019

doi: https://doi.org/10.12669/pjms.35.6.1529
Unfolding the enigma of lamina cribrosa morphometry and its association with glaucoma
Authors: Saba Ayesha , Usmani Ambreen Usmani , Islam Qamarul , Assad Tahira
Published: October 2019

Primary open angle glaucoma (POAG) is worldwide prevalent ailment, affecting millions, and leading irreversible cause of blindness. The treatment strategies revolve around one modifiable factor, elevated intraocular pressure (IOP), despite POAG presenting with normal IOP. Emphasis is put forth in recent past detecting structural elements of glaucoma; lamina cribrosa (LC) is found to be a promising prospect. Morphological alterations of LC are implicated as early sign before onset of glaucomatous optic neuropathy (GON). In this review, the authors explored scientific works from 1976 till 2018 through Google, Google Scholar, PubMed, HEC Digital Library, Springerlink, and PakMedinet in four months’ time, extracted structural features of LC, its measurable attributes, fresh innovations employed for in-vivo visualization and clinical signs aiding in establishing diagnosis of glaucoma which will assist as a prophylactic measure against GON. No such work has ever been done in South-East Asia including our country. So LC opens a new horizon for research in Pakistan.

doi: https://doi.org/10.12669/pjms.35.6.568

How to cite this:Saba A, Usmani A, Qamar-Ul-Islam, Assad T. Unfolding the enigma of lamina cribrosa morphometry and its association with glaucoma. Pak J Med Sci. 2019;35(6):1730-1735. doi: https://doi.org/10.12669/pjms.35.6.568

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.