Drosophila medulla neuroblast termination via apoptosis, differentiation and gliogenic switch is scheduled by the depletion of the neuroepithelial stem cell pool.

The brain is consisted of diverse neurons arising from a limited number of neural stem cells. Drosophila neural stem cells called neuroblasts (NBs) produces specific neural lineages of various lineage sizes depending on their location in the brain. In the Drosophila visual processing centre - the optic lobes (OLs), medulla NBs derived from the neuroepithelium (NE) give rise to neurons and glia cells of the medulla cortex. The timing and the mechanisms responsible for the cessation of medulla NBs are so far not known. In this study, we show that the termination of medulla NBs during early pupal development is determined by the exhaustion of the NE stem cell pool. Hence, altering NE-NB transition during larval neurogenesis disrupts the timely termination of medulla NBs. Medulla NBs terminate neurogenesis via a combination of apoptosis, terminal symmetric division via Prospero, and a switch to gliogenesis via Glial Cell Missing (Gcm), however, these processes occur independently of each other. We also show that temporal progression of the medulla NBs is mostly not required for their termination. As the Drosophila OL shares a similar mode of division with mammalian neurogenesis, understanding when and how these progenitors cease proliferation during development can have important implications for mammalian brain size determination and regulation of its overall function.

Cost-utility analysis of community-based interventions for hypertension control in Vietnam.

Between 2010 and 2011, stakeholders implemented a multi-faceted community-based intervention in response to the escalating issue of uncontrolled hypertension in Hung Yen province, Vietnam. This initiative integrated expanded community health worker services, home blood pressure self-monitoring, and a unique "storytelling intervention" into routine clinical care. From the limited societal perspective, our study evaluates the cost-effectiveness of this intervention using a Markov model with a one-year cycle over a lifetime horizon. The analysis, based on a cohort of 671 patients, reveals a lifetime incremental cost of approximately VND 90.37 million (USD 3,930) per quality-adjusted life year (QALY) gained. With a willingness to pay at three times GDP (VND 259.2 million per QALY), the intervention proves cost-effective 80% of the time. This research underscores the potential of the community-based approach to effectively control hypertension, offering valuable insights into its broader implications for public health.

Cost-effectiveness of one-year adjuvant trastuzumab therapy in treatment for early-stage breast cancer patients with HER2+ in Vietnam.

BACKGROUND: In Vietnam, trastuzumab is included in social health insurance's benefits package with a reimbursement rate of 60%, but policymakers have been concerned about its cost-effectiveness. The research aims to evaluate the cost-effectiveness of one-year adjuvant trastuzumab therapy for early-stage breast cancer patients with human epidermal growth receptor 2 (HER2+) from a societal perspective. METHOD: A Markov model was developed and validated to estimate the lifetime cost and effectiveness (using life year and quality-adjusted life year) of one-year adjuvant trastuzumab therapy compared to chemotherapy (using paclitaxel) alone. Treatment efficacy and transition probabilities were estimated based on published trials (i.e., N9831, NSABP B-31, HERA, and BCIRG 006). Local cost and utility data were employed to capture the Vietnam context. One-way sensitivity analysis, probabilistic sensitivity analysis, threshold, and scenario analysis were also performed. RESULTS: One-year adjuvant trastuzumab therapy combined with chemotherapy compared to chemotherapy alone yielded an additional cost of 888,453,971VND (39,062 US$) with an additional 3.09 LYs and 1.61 QALYs, resulting in an ICER of 287,390,682 VND (12,635 US$) per LY gained, or 519,616,972 VND (22,845 US$) per QALY gained. The ICER exceeds the cost-effective threshold of 1- and 3-time GDP per capita by 6.3 and 2.1 times. The probabilistic sensitivity analysis shows similar results. According to one-way sensitivity analysis, ICERs were driven mainly by transition probabilities and trastuzumab price. One-year adjuvant trastuzumab therapy would be cost-effective at the 3-time GDP per capita threshold if the cost of Herceptin 150mg and 450mg vials were reduced by 56% and 54%, correspondingly. CONCLUSION: In Vietnam, one-year adjuvant trastuzumab therapy for early-stage breast cancer with HER2+ is not cost-effective. The research provided reliable and updated evidence to support policymakers in revising the health insurance benefit package. The policymakers should consider the options to reduce the cost of trastuzumab (e.g., regarding the use of trastuzumab biosimilars, price negotiation options, and options of optimizing the use of Herceptin vials among concurrent hospitalized breast cancer patients).

Asian Zika virus can acquire generic African-lineage mutations during in utero infection.

The Zika virus 2015 epidemic showed an unusual phenotype for human flaviviruses, specifically fetal infection. We previously showed that in utero inoculation with the Asian Zika virus isolated from the human sample causes persistent infection in porcine fetuses. Here, we characterized the evolution of the Asian Zika virus in the fetal brain and placenta. Interestingly, the Asian Zika virus acquired generic African lineage K101R (A408G) and R1609 K (G4932A) mutations during in utero infection. Both African mutations were nonsynonymous and had a high frequency of nearly 100% in the fetal brain. Then, we synthetically generated the wild-type Asian variant and fetal brain-specific variant with generic African-lineage K101R and R1609 K mutations. In mosquito C6/36 cells, but not in human and pig cells, the fetal brain-specific variant showed higher virus loads compared to the Asian wild-type prototype. While in utero infection with both variants caused comparable virus loads in the placenta and amniotic fluids, fetuses injected with the fetal brain-specific variant had the trend to higher virus loads in lymph nodes. Also, introduced K101R and R1609 K mutations were stable and had high nearly 100% frequency at 28 days after in utero inoculation in both directly injected and trans-infected fetuses. These findings evoke concerns because Zika persists in pig herds and mosquitoes on farms in Mexico. It will be essential to identify how persistent in utero infection affects virus evolution and whether in utero-emerged Zika variants have the potential for shedding into the environment, more efficient transmission, and more aggressive infection phenotypes.

Dedifferentiation-derived neural stem cells exhibit perturbed temporal progression.

Dedifferentiation is the reversion of mature cells to a stem cell-like fate, whereby gene expression programs are altered and genes associated with multipotency are (re)expressed. Misexpression of multipotency factors and pathways causes the formation of ectopic neural stem cells (NSCs). Whether dedifferentiated NSCs faithfully produce the correct number and types of progeny, or undergo timely terminal differentiation, has not been assessed. Here, we show that ectopic NSCs induced via bHLH transcription factor Deadpan (Dpn) expression fail to undergo appropriate temporal progression by constantly expressing mid-temporal transcription factor(tTF), Sloppy-paired 1/2 (Slp). Consequently, this resulted in impaired terminal differenation and generated an excess of Twin of eyeless (Toy)-positive neurons at the expense of Reversed polarity (Repo)-positive glial cells. Preference for a mid-temporal fate in these ectopic NSCs is concordant with an enriched binding of Dpn at mid-tTF loci and a depletion of Dpn binding at early- and late-tTF loci. Retriggering the temporal series via manipulation of the temporal series or cell cycle is sufficient to reinstate neuronal diversity and timely termination.

Deficiency of leukocyte-specific protein 1 (LSP1) alleviates asthmatic inflammation in a mouse model.

BACKGROUND: Asthma is a major cause of morbidity and mortality in humans. The mechanisms of asthma are still not fully understood. Leukocyte-specific protein-1 (LSP-1) regulates neutrophil migration during acute lung inflammation. However, its role in asthma remains unknown. METHODS: An OVA-induced mouse asthma model in LSP1-deficient (Lsp1-/-) and wild-type (WT) 129/SvJ mice were used to test the hypothesis that the absence of LSP1 would inhibit airway hyperresponsiveness and lung inflammation. RESULTS: Light and electron microscopic immunocytochemistry and Western blotting showed that, compared with normal healthy lungs, the levels of LSP1 were increased in lungs of OVA-asthmatic mice. Compared to Lsp1-/- OVA mice, WT OVA mice had higher levels of leukocytes in broncho-alveolar lavage fluid and in the lung tissues (P < 0.05). The levels of OVA-specific IgE but not IgA and IgG1 in the serum of WT OVA mice was higher than that of Lsp1-/- OVA mice (P < 0.05). Deficiency of LSP1 significantly reduced the levels of IL-4, IL-5, IL-6, IL-13, and CXCL1 (P < 0.05) but not total proteins in broncho-alveolar lavage fluid in asthmatic mice. The airway hyper-responsiveness to methacholine in Lsp1-/- OVA mice was improved compared to WT OVA mice (P < 0.05). Histology revealed more inflammation (inflammatory cells, and airway and blood vessel wall thickening) in the lungs of WT OVA mice than in those of Lsp1-/- OVA mice. Finally, immunohistology showed localization of LSP1 protein in normal and asthmatic human lungs especially associated with the vascular endothelium and neutrophils. CONCLUSION: These data show that LSP1 deficiency reduces airway hyper-responsiveness and lung inflammation, including leukocyte recruitment and cytokine expression, in a mouse model of asthma.

Non-autonomous regulation of neurogenesis by extrinsic cues: a Drosophila perspective.

The formation of a functional circuitry in the central nervous system (CNS) requires the correct number and subtypes of neural cells. In the developing brain, neural stem cells (NSCs) self-renew while giving rise to progenitors that in turn generate differentiated progeny. As such, the size and the diversity of cells that make up the functional CNS depend on the proliferative properties of NSCs. In the fruit fly Drosophila, where the process of neurogenesis has been extensively investigated, extrinsic factors such as the microenvironment of NSCs, nutrients, oxygen levels and systemic signals have been identified as regulators of NSC proliferation. Here, we review decades of work that explores how extrinsic signals non-autonomously regulate key NSC characteristics such as quiescence, proliferation and termination in the fly.

Integrin alpha-v/beta3 expression in equine lungs and jejunum.

Integrin alpha-v/beta3 (αvß3) recognizes arginine-glycine-aspartic acid (RGD) sequences and has important functions in cell adhesion, signaling, and survival. However, the expression of integrin αvß3 in the equine lungs and jejunum is not well understood. The objective of this study was to explore the hitherto unknown expression of integrin αvß3 in the lungs and jejuna of the horse using light and electron immunocytochemistry. Immunohistochemistry showed integrin αvß3 on the epithelium, the immune cells in Peyer's patches, the smooth muscle, and the endothelium of equine jejuna. In equine lungs, we recognized integrin αvß3 on the endothelium of blood vessels, the alveolar septa, the bronchial lymph nodes, and the cartilages, although the expression of integrin αvß3 was weak on the epithelium of bronchioles. In conclusion, these are the first data to show the expression of integrin αvß3 in equine lungs and jejuna.

L'intégrine alpha-v/beta3 (αvß3) reconnaît les séquences arginine-glycine-acide aspartique (RGD) et a d'importantes fonctions dans l'adhésion cellulaire, la signalisation et la survie. Toutefois, l'expression de l'intégrine αvß3 dans les poumons et le jéjunum équins n'est pas bien comprise. L'objectif de la présente étude était d'explorer l'expression inconnue jusqu'à ce jour de l'intégrine αvß3 dans les poumons et le jéjunum du cheval en utilisant l'immunohistochimie photonique et électronique. L'immunohistochimie a montré l'intégrine αvß3 sur l'épithélium, les cellules immunitaires des plaques de Peyer, le muscle lisse et l'endothélium du jéjunum équin. Dans les poumons équins, nous avons reconnu l'intégrine αvß3 sur l'endothélium des vaisseaux sanguins, les septas alvéolaires, les noeuds lymphatique bronchiaux et les cartilages, quoique l'expression de l'intégrine αvß3 était faible sur l'épithélium des bronchioles. En conclusion, ceci représente les premiers résultats qui démontrent l'expression de l'intégrine αvß3 dans les poumons et le jéjunum équins.(Traduit par Docteur Serge Messier).

Retrospective study of irrational prescribing in French paediatric hospital: prevalence of inappropriate prescription detected by Pediatrics: Omission of Prescription and Inappropriate prescription (POPI) in the emergency unit and in the ambulatory setting.

BACKGROUND AND OBJECTIVE: Pediatrics: Omission of Prescription and Inappropriate prescription (POPI) is the first detection tool for potentially inappropriate medicines (PIMs) and potentially prescribing omissions (PPOs) in paediatrics. The aim of this study was to evaluate the prevalence of PIM and PPO detected by POPI regarding prescriptions in hospital and for outpatients. The second objective is to determine the risk factors related to PIM and PPO. DESIGN: A retrospective, descriptive study was conducted in the emergency department (ED) and community pharmacy (CP) during 6 months. POPI was used to identify PIM and PPO. SETTING: Robert-Debré Hospital (France) and Albaret community pharmacy (Seine and Marne). PARTICIPANTS: Patients who were under 18 years old and who had one or more drugs prescribed were included. Exclusion criteria consisted of inaccessible medical records for patients consulted in ED and prescription without drugs for outpatients. PRIMARY AND SECONDARY OUTCOME MEASURES: PIM and PPO rate and risk factors. RESULTS: At the ED, 18 562 prescriptions of 15 973 patients and 4780 prescriptions of 2225 patients at the CP were analysed. The PIM rate and PPO rate were, respectively, 2.9% and 2.3% at the ED and 12.3% and 6.1% at the CP. Respiratory and digestive diseases had the highest rate of PIM. CONCLUSION: This is the first study to assess the prevalence of PIM and PPO detected by POPI in a paediatric population. This study assessed PIMs or PPOs within a hospital and a community pharmacy. POPI could be used to improve drug use and patient care and to limit hospitalisation and adverse drug reaction. A prospective multicentric study should be conducted to evaluate the impact and benefit of implementing POPI in clinical practice.

Leukocyte-specific protein 1 regulates neutrophil recruitment in acute lung inflammation.

The mechanisms of excessive migration of activated neutrophils into inflamed lungs, credited with tissue damage, are not fully understood. We explored the hitherto unknown expression of leukocyte-specific protein 1 (LSP1) in human and mouse lungs and neutrophils and examined its role in neutrophil migration in acute lung inflammation. Autopsied septic human lungs showed increased LSP1 labeling in epithelium, endothelium, and leukocytes, including in their nuclei compared with normal lungs. We induced acute lung inflammation through intranasal administration of E. coli lipopolysaccharide (LPS) (80 µg) in LSP1-deficient (Lsp1(-/-)) and wild-type (WT) 129/SvJ mice. Immunocytochemistry and Western blots showed increased expression of LSP1 and phosphorylated LSP1 in lungs of LPS-treated WT mice. Histology showed more congestion, inflammation, and Gr-1(+) neutrophils in lung of WT mice than Lsp1(-/-) mice. LPS-treated WT mice had significantly more neutrophils in bronchoalveolar lavage (BAL) and myeloperoxidase levels in lungs compared with Lsp1(-/-) mice. However, there were no differences in lung tissue and BAL concentrations of keratinocyte-derived chemokine, monocyte chemoattractant protein-1, macrophage inflammatory protein-1α and -1ß, vascular permeability, and phosphorylated p38 MAPK between LPS-treated WT and Lsp1(-/-) mice, whereas TNF-α concentration was higher in BAL fluid from LPS-treated WT. Immunoelectron microscopy showed increased LSP1 in the nuclei of LPS-treated neutrophils. We also found increased levels of phosphorylated LSP1 associated with plasma membrane, nucleus, and cytosol at various times after LPS treatment of murine bone marrow-derived neutrophils, suggesting its role in modulation of neutrophil cytoskeleton and the membrane. These data collectively show increased expression of LSP1 in inflamed mouse and human lungs and its role in neutrophil recruitment and lung inflammation.

A systematic review of scope and quality of health economic evaluation studies in Vietnam.

INTRODUCTION: The application of health economic evaluation (HEE) evidence can play an important role in strategic planning and policy making. This study aimed to assess the scope and quality of existing research, with the goal of elucidating implications for improving the use of HEE evidence in Vietnam. METHODS: A comprehensive search strategy was developed to search medical online databases (Medline, Google Scholar, and Vietnam Medical Databases) to select all types of HEE studies except cost-only analyses. Two researchers assessed the quality of selected studies using the Quality of Health Economic Studies (QHES) instrument. RESULTS: We selected 26 studies, including 6 published in Vietnam. The majority of these studies focused on infectious diseases (14 studies), with HIV being the most common topic (5 studies). Most papers were cost-effectiveness studies that measured health outcomes using DALY units. Using QHES, we found that the overall quality of HEE studies published internationally was much higher (mean score 88.7+13.3) than that of those published in Vietnam (mean score 67.3+22.9). Lack of costing perspectives, reliable data sources and sensitivity analysis were the main shortcomings of the reviewed studies. CONCLUSION: This review indicates that HEE studies published in Vietnam are limited in scope and number, as well as by several important technical errors or omissions. It is necessary to formalize the process of health economic research in Vietnam and to institutionalize the links between researchers and policy-makers. Additionally, the quality of HEE should be enhanced through education about research techniques, and the implementation of standard HEE guidelines.

Electrochemical response of carbon paste electrode modified with mixture of titanium dioxide/zirconium dioxide in the detection of heavy metals: lead and cadmium.

A novel carbon modified electrode was developed by incorporating titanium dioxide/zirconium dioxide into the graphite carbon paste electrode to detect heavy metals-cadmium and lead. In this work, the development of the novel titanium dioxide/zirconium dioxide modified carbon paste electrode was studied to determine the optimum synthesis conditions related to the temperature, heating duration, amount and ratio of titanium dioxide/zirconium dioxide, and amount of surfactant, to create the most reproducible results. Using cyclic voltammetric (CV) analysis, this study has proven that the novel titanium dioxide/zirconium dioxide can be utilized to detect heavy metals-lead and cadmium, at relatively low concentrations (7.6×10(-6) M and 1.1×10(-5) M for Pb and Cd, respectively) at optimum pH value (pH=3). From analyzing CV data the optimal electrodes surface area was estimated to be 0.028 (±0.003) cm(2). Also, under the specific experimental conditions, electron transfer coefficients were estimated to be 0.44 and 0.33 along with the heterogeneous electron transfer rate constants of 5.64×10(-3) and 2.42×10(-3) (cm/s) for Pb and Cd, respectively.