Nguyen Mai

Gingipains from Porphyromonas gingivalis drive Alzheimer’s pathology and can be blocked with small-molecule inhibitors.

Abstract Background MitoQ is a mitochondria-targeted derivative of the antioxidant ubiquinone, with antioxidant and anti-apoptotic functions. Reactive oxygen species are involved in many inflammatory diseases including inflammatory bowel disease. In this study, we assessed the therapeutic effects of MitoQ in a mouse model of experimental colitis and investigated the possible mechanisms underlying its effects on intestinal inflammation. Methods Reactive oxygen species levels and mitochondrial function were measured in blood mononuclear cells of patients with inflammatory bowel disease. The effects of MitoQ were evaluated in a dextran sulfate sodium-induced colitis mouse model. Clinical and pathological markers of disease severity and oxidative injury, and levels of inflammatory cytokines in mouse colonic tissue were measured. The effect of MitoQ on inflammatory cytokines released in the human macrophage-like cell line THP-1 was also analyzed. Results Cellular and mitochondrial reactive oxygen species levels in mononuclear cells were significantly higher in patients with inflammatory bowel disease ( P <0.003, cellular reactive oxygen species; P <0.001, mitochondrial reactive oxygen species). MitoQ significantly ameliorated colitis in the dextran sulfate sodium-induced mouse model in vivo , reduced the increased oxidative stress response (malondialdehyde and 3-nitrotyrosine formation), and suppressed mitochondrial and histopathological injury by decreasing levels of inflammatory cytokines IL-1 beta and IL-18 ( P < 0 . 001 and P <0.01 respectively). By decreasing mitochondrial reactive oxygen species, MitoQ also suppressed activation of the NLRP3 inflammasome that was responsible for maturation of IL-1 beta and IL-18. In vitro studies demonstrated that MitoQ decreases IL-1 beta and IL-18 production in human THP-1 cells. Conclusion Taken together, our results suggest that MitoQ may have potential as a novel therapeutic agent for the treatment of acute phases of inflammatory bowel disease.

Rationale: Oxidized palmitoyl arachidonyl phosphatidylcholine (Ox-PAPC) accumulates in atherosclerotic lesions, is proatherogenic, and influences the expression of more than 1000 genes in endothelial cells. Objective: To elucidate the major pathways involved in Ox-PAPC action, we conducted a systems analysis of endothelial cell gene expression after exposure to Ox-PAPC. Methods and Results: We used the variable responses of primary endothelial cells from 149 individuals exposed to Ox-PAPC to construct a network that consisted of 11 groups of genes, or modules. Modules were enriched for a broad range of Gene Ontology pathways, some of which have not been identified previously as major Ox-PAPC targets. Further validating our method of network construction, modules were consistent with relationships established by cell biology studies of Ox-PAPC effects on endothelial cells. This network provides novel hypotheses about molecular interactions, as well as candidate molecular regulators of inflammation and atherosclerosis. We validated several hypotheses based on network connections and genomic association. Our network analysis predicted that the hub gene CHAC1 (cation transport regulator homolog 1) was regulated by the ATF4 (activating transcription factor 4) arm of the unfolded protein response pathway, and here we showed that ATF4 directly activates an element in the CHAC1 promoter. We showed that variation in basal levels of heme oxygenase 1 (HMOX1) contribute to the response to Ox-PAPC, consistent with its position as a hub in our network. We also identified G-protein–coupled receptor 39 (GPR39) as a regulator of HMOX1 levels and showed that it modulates the promoter activity of HMOX1. We further showed that OKL38/OSGN1 (oxidative stress–induced growth inhibitor), the hub gene in the blue module, is a key regulator of both inflammatory and antiinflammatory molecules. Conclusions: Our systems genetics approach has provided a broad view of the pathways involved in the response of endothelial cells to Ox-PAPC and also identified novel regulatory mechanisms.

Background Porphyromonas gingivalis (P. gingivalis) and its gingipain virulence factors have been identified as pathogenic effectors in Alzheimer's disease (AD). In a recent study we demonstrated the presence of gingipains in over 90% of postmortem AD brains, with gingipains localizing to the cytoplasm of neurons. However, infection of neurons by P. gingivalis has not been previously reported. Objective To demonstrate intraneuronal P. gingivalis and gingipain expression in vitro after infecting neurons derived from human inducible pluripotent stem cells (iPSC) with P. gingivalis for 24, 48, and 72 h. Methods Infection was characterized by transmission electron microscopy, confocal microscopy, and bacterial colony forming unit assays. Gingipain expression was monitored by immunofluorescence and RT-qPCR, and protease activity monitored with activity-based probes. Neurodegenerative endpoints were assessed by immunofluorescence, western blot, and ELISA. Results Neurons survived the initial infection and showed time dependent, infection induced cell death. P. gingivalis was found free in the cytoplasm or in lysosomes. Infected neurons displayed an accumulation of autophagic vacuoles and multivesicular bodies. Tau protein was strongly degraded, and phosphorylation increased at T231. Over time, the density of presynaptic boutons was decreased. Conclusion P. gingivalis can invade and persist in mature neurons. Infected neurons display signs of AD-like neuropathology including the accumulation of autophagic vacuoles and multivesicular bodies, cytoskeleton disruption, an increase in phospho-tau/tau ratio, and synapse loss. Infection of iPSC-derived mature neurons by P. gingivalis provides a novel model system to study the cellular mechanisms leading to AD and to investigate the potential of new therapeutic approaches.

Aggressive and recurrent gynecological cancers are associated with worse prognosis and a lack of effective therapeutic response. Ovarian cancer (OC) patients are often diagnosed in advanced stages, when drug resistance, angiogenesis, relapse, and metastasis impact survival outcomes. Currently, surgical debulking, radiotherapy, and/or chemotherapy remain the mainstream treatment modalities; however, patients suffer unwanted side effects and drug resistance in the absence of targeted therapies. Hence, it is urgent to decipher the complex disease biology and identify potential biomarkers, which could greatly contribute to making an early diagnosis or predicting the response to specific therapies. This review aims to critically discuss the current therapeutic strategies for OC, novel drug-delivery systems, and potential biomarkers in the context of genetics and molecular research. It emphasizes how the understanding of disease biology is related to the advancement of technology, enabling the exploration of novel biomarkers that may be able to provide more accurate diagnosis and prognosis, which would effectively translate into targeted therapies, ultimately improving patients' overall survival and quality of life.

Abstract Severe sepsis, a systemic inflammatory response to infection, is an increasing cause of morbidity in intensive care units. During sepsis, the vasculature is profoundly altered, leading to release of microbial virulence factors and proinflammatory mediators to surrounding tissue, causing severe systemic inflammatory responses and hypoxic injury of multiple organs. To date, multiple studies have explored pathologic conditions in many vital organs, including lungs, liver, and kidneys. Although data suggest that sepsis is emerging as a key driver of chronic brain dysfunction, the immunological consequence of severe inflammatory responses in the brain remain poorly understood. In this study, we used C57BL/6 sepsis mouse models to establish a disease phenotype in which septic mice with various degrees of severity recover. In the early phases of sepsis, monocytes infiltrate the brain with significantly elevated proinflammatory cytokine levels. In recovered animals, monocytes return to vehicle levels, but the number of brain-resident microglia is significantly increased in the cortex, the majority of which remain activated. The increase in microglia number is mainly due to self-proliferation, which is completely abolished in CCR2 knockout mice. Collectively our data suggest that early monocyte infiltration causes permanent changes to microglia during sepsis, which may ultimately dictate the outcome of future infections and neuropathological diseases.

Doxorubicin (DOX) is a chemotherapeutic drug that is used to treat many cancers, but its use is limited by cardiotoxic side effect. Carbonyl reductase 1 (CBR1) is an NADPH-dependent oxidoreductase that reduces DOX to doxorubicinol (DOXOL), a less potent derivative that is responsible for DOX cardiotoxicity. Thus, we aimed to demonstrate that inhibition of CBR1 enhances the chemotherapeutic efficacy of DOX and attenuates cardiotoxicity.Pharmacological or genetic inhibition of CBR1 improved the anticancer effects of DOX in preclinical models of breast cancer. RNA interference or chemical inhibition of CBR1 improved the anticancer effect of DOX in breast cancer. Moreover, CBR1 overexpression enabled breast cancer cells to obtain chemotherapeutic resistance to DOX treatment. Intriguingly, inhibition of CBR1 decreased DOX-induced cardiotoxicity in animal model. Innovation and Conclusions: Inhibition of CBR1 increases chemotherapeutic efficacy of DOX and reduces cardiotoxicity by blocking DOX reduction to DOXOL. Therefore, we offer preclinical proof-of-concept for a combination strategy to safely leverage the efficacy of doxorubicin by blunting its cardiotoxic effects that limit use of this cytotoxic agent used widely in the oncology clinic. Antioxid. Redox Signal. 26, 70-83.

Systemic inflammation and multi-organ failure represent hallmarks of the post-cardiac arrest syndrome (PCAS) and predict severe neurological injury and often fatal outcomes. Current interventions for cardiac arrest focus on the reversal of precipitating cardiac pathologies and the implementation of supportive measures with the goal of limiting damage to at-risk tissue. Despite the widespread use of targeted temperature management, there remain no proven approaches to manage reperfusion injury in the period following the return of spontaneous circulation. Recent evidence has implicated the lung as a moderator of systemic inflammation following remote somatic injury in part through effects on innate immune priming. In this review, we explore concepts related to lung-dependent innate immune priming and its potential role in PCAS. Specifically, we propose and investigate the conceptual model of lung–brain coupling drawing from the broader literature connecting tissue damage and acute lung injury with cerebral reperfusion injury. Subsequently, we consider the role that interventions designed to short-circuit lung-dependent immune priming might play in improving patient outcomes following cardiac arrest and possibly other acute neurological injuries.

Post-ischemic neurodegeneration remains the principal cause of mortality following cardiac resuscitation. Recent studies have implicated gastrointestinal ischemia in the sepsis-like response associated with the post-cardiac arrest syndrome (PCAS). However, the extent to which the resulting low-grade endotoxemia present in up to 86% of resuscitated patients affects cerebral ischemia-reperfusion injury has not been investigated. Here we report that a single injection of low-dose lipopolysaccharide (50 μg/kg, IP) delivered after global cerebral ischemia (GCI) induces blood-brain barrier permeability, microglial activation, cortical injury, and functional decline in vivo, compared to ischemia alone. And while GCI was sufficient to induce neutrophil (PMN) activation and recruitment to the post-ischemic CNS, minimal endotoxemia exhibited synergistic effects on markers of systemic inflammation including PMN priming, lung damage, and PMN burden within the lung and other non-ischemic organs including the kidney and liver. Our findings predict that acute interventions geared towards blocking the effects of serologically occult endotoxemia in survivors of cardiac arrest will limit delayed neurodegeneration, multi-organ dysfunction and potentially other features of PCAS. This work also introduces lung-brain coupling as a novel therapeutic target with broad effects on innate immune priming and post-ischemic neurodegeneration following cardiac arrest and related cerebrovascular conditions.

Abstract COR388, a small‐molecule lysine‐gingipain inhibitor, is currently being investigated in a Phase 2/3 clinical trial for Alzheimer's disease (AD) with exploratory endpoints in periodontal disease. Gingipains are produced by two species of bacteria, Porphyromonas gingivalis and Porphyromonas gulae , typically associated with periodontal disease and systemic infections in humans and dogs, respectively. P. gulae infection in dogs is associated with periodontal disease, which provides a physiologically relevant model to investigate the pharmacology of COR388. In the current study, aged dogs with a natural oral infection of P. gulae and periodontal disease were treated with COR388 by oral administration for up to 90 days to assess lysine‐gingipain target engagement and reduction of bacterial load and downstream pathology. In a 28‐day dose‐response study, COR388 inhibited the lysine‐gingipain target and reduced P. gulae load in saliva, buccal cells, and gingival crevicular fluid. The lowest effective dose was continued for 90 days and was efficacious in continuous reduction of bacterial load and downstream periodontal disease pathology. In a separate histology study, dog brain tissue showed evidence of P. gulae DNA and neuronal lysine‐gingipain, demonstrating that P. gulae infection is systemic and spreads beyond its oral reservoir, similar to recent observations of P. gingivalis in humans. Together, the pharmacokinetics and pharmacodynamics of COR388 lysine‐gingipain inhibition, along with reduction of bacterial load and periodontal disease in naturally occurring P. gulae infection in the dog, support the use of COR388 in targeting lysine‐gingipain and eliminating P. gingivalis infection in humans.

Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has become one of the most serious public health crises worldwide. Most infected people are asymptomatic but are still able to spread the virus. People with mild or moderate illnesses are likely to recover without hospitalization, while critically ill patients face a higher risk of organ injury or even death. In this study, we aimed to identify a novel biomarker that can predict the severity of COVID-19 patients. Clinical information and RNA-seq data of leukocytes from whole blood samples with and without a COVID-19 diagnosis (n = 100 and 26, respectively) were retrieved from the National Center for Biotechnology Information Gene Expression Omnibus database. Raw data were processed using the Transcripts Per Million (TPM) method and then transformed using log2 (TPM+1) for normalization. The CD24-CSF1R index was established. Violin plots, Kaplan-Meier curves, ROC curves, and multivariate Cox proportional hazards regression analyses were performed to evaluate the prognostic value of the established index. The CD24-CSF1R index was significantly associated with ICU admission (n = 50 ICU, 50 non-ICU) and ventilatory status (n = 42 ventilation, 58 non-ventilation) with p = 4.186e-11 and p = 1.278e-07, respectively. The ROC curve produced a relatively accurate prediction of ICU admission with an AUC of 0.8524. Additionally, patients with a high index had significantly fewer mechanical ventilation-free days than patients with a low index (p = 6.07e-07). Furthermore, the established index showed a strong prognostic ability for the risk of using a ventilator in the multivariate Cox regression model (p < 0.001). The CD24-CSF1R index was significantly associated with COVID-19 severity. The established index could have potential implications for prognosis, disease severity stratification, and clinical management.

Background Though the epidemiology of craniomaxillofacial (CMF) fractures has been well documented at urban hospitals, the characteristics of these fractures in rural hospitals have not been well studied. Purpose The purpose of this study is to report on the epidemiology of CMF fractures at a regional Level 1 trauma center serving a large rural population in central Illinois. Study Design, Setting, Sample This is a retrospective cohort study at a community-based regional tertiary referral center that serves a predominantly rural population. Inclusion criteria comprised patients with radiologically confirmed CMF fractures between 2015 and 2019. Patients with incomplete medical records were excluded. Predictor Variable Predictor variables included demographics (age, admission source, race, and sex) and etiology of CMF fracture (assault/domestic violence, all-terrain vehicle/off-road, falls, farm-related, motor vehicle collisions, gunshot wound, and others). Main Outcome Variable The primary outcome variable was the CMF anatomic location including nasal bone, orbit, mandible, malar/maxillary, and other CMF fractures. Covariates The covariates are not applicable. Analyses Descriptive statistics were used to summarize a sample of the population characteristics. Wilcoxon ranked sign tests and χ2 tests of independence were used to assess for statistically significant associations between select variables of interest. Statistical significance was defined as P < .05. Results Between 2015 and 2019, a total of 2,334 patients presented to the emergency department with a CMF fracture. After applying the inclusion/exclusion criteria, the final sample was composed of 1,844 patients for the management of 2,405 CMF fractures. The majority of patients were male(62.0%) and young adults (aged 18-39) had the highest number of CMF fractures (819) relative to all other age groups. The most common fracture etiology was fall(37.3%), and nasal bone fractures represented the most common fracture location(41.6%). χ2 analyses revealed statistically significant associations between the anatomic location of CMF fracture incurred, and differing categories of age, admission source, race, sex, and etiology. Conclusion and Relevance Our study shows that patients seen at our Midwestern Level 1 trauma center are more likely to present with nasal bone and malar/maxillary fractures due to falls. In studies based in urban centers, patients are likely to present with orbital and mandibular fractures due to falls and assault. Though the epidemiology of craniomaxillofacial (CMF) fractures has been well documented at urban hospitals, the characteristics of these fractures in rural hospitals have not been well studied. The purpose of this study is to report on the epidemiology of CMF fractures at a regional Level 1 trauma center serving a large rural population in central Illinois. This is a retrospective cohort study at a community-based regional tertiary referral center that serves a predominantly rural population. Inclusion criteria comprised patients with radiologically confirmed CMF fractures between 2015 and 2019. Patients with incomplete medical records were excluded. Predictor variables included demographics (age, admission source, race, and sex) and etiology of CMF fracture (assault/domestic violence, all-terrain vehicle/off-road, falls, farm-related, motor vehicle collisions, gunshot wound, and others). The primary outcome variable was the CMF anatomic location including nasal bone, orbit, mandible, malar/maxillary, and other CMF fractures. The covariates are not applicable. Descriptive statistics were used to summarize a sample of the population characteristics. Wilcoxon ranked sign tests and χ2 tests of independence were used to assess for statistically significant associations between select variables of interest. Statistical significance was defined as P < .05. Between 2015 and 2019, a total of 2,334 patients presented to the emergency department with a CMF fracture. After applying the inclusion/exclusion criteria, the final sample was composed of 1,844 patients for the management of 2,405 CMF fractures. The majority of patients were male(62.0%) and young adults (aged 18-39) had the highest number of CMF fractures (819) relative to all other age groups. The most common fracture etiology was fall(37.3%), and nasal bone fractures represented the most common fracture location(41.6%). χ2 analyses revealed statistically significant associations between the anatomic location of CMF fracture incurred, and differing categories of age, admission source, race, sex, and etiology. Our study shows that patients seen at our Midwestern Level 1 trauma center are more likely to present with nasal bone and malar/maxillary fractures due to falls. In studies based in urban centers, patients are likely to present with orbital and mandibular fractures due to falls and assault.

It is well established that reactive oxygen species (ROS) are essential signaling molecules for muscle differentiation. Carbonyl reductase 1 (CBR1) reduces highly reactive lipid aldehydes and catalyzes a variety of endogenous and xenobiotic carbonyl compounds. However, the role of CBR1 in muscle differentiation remains unclear. In this study, we found that CBR1 plays a crucial role in differentiation of muscle-derived C2C12 cells. Our results clearly show that CBR1 is upregulated at the transcript level during differentiation. Consistently, CBR1 was increased during skeletal muscle regeneration in tibialis anterior muscle after injury induced by cardiotoxin. The transcriptional upregulation of CBR1 was found to be controlled by nuclear factor erythroid 2-related factor 2 (Nrf2), and Nrf2 knockdown with specific siRNA inhibited muscle differentiation. Furthermore, intracellular ROS levels and lipid peroxidation were increased in cells transfected with CBR1 siRNA, or in cells treated with the selective CBR1 inhibitor, Hydroxy-PP-Me. Subsequently, the increased ROS levels diminished muscle cell differentiation. All together, we conclude that CBR1 plays a critical role in controlling redox balance and detoxifying lipid peroxidation during muscle differentiation and regeneration.

Gliomas are the most common and aggressive primary tumors in adults. The current approaches, such as histological classification and molecular genetics, have limitation in prediction of individual therapeutic outcomes due to heterogeneity within the tumor groups. Recent studies have proposed several gene signatures to predict glioma's prognosis. However, most of the gene expression profiling studies have been performed on relatively small number of patients and combined probes from diverse microarray chips. Here, we identified prognostic 89 common genes from diverse microarray chips. The 89-gene signature classified patients into good and bad prognostic groups which differed in the overall survival significantly, reflecting the biological characteristics and heterogeneity. The robustness and accuracy of the gene signature as an independent prognostic factor was validated in three microarray and one RNA-seq data sets independently. By incorporating into histological classification and molecular marker, the 89-gene signature could further stratify patients with 1p/19q co-deletion and IDH1 mutation. Additionally, subset analyses suggested that the 89-gene signature could predict patients who would benefit from adjuvant chemotherapy. Conclusively, we propose that the 89-gene signature would have an independent and accurate prognostic value for clinical use. This study also offers opportunities for novel targeted treatment of individual patients.

The porcine reproductive and respiratory syndrome virus (PRRSV) causes more economic losses in the swine industry than any other virus. This study aimed to investigate the genetic diversity of PRRSV to assist in evaluating the effectiveness of PRRS vaccines. Twenty-eight samples from clinical cases were collected from 19 farms in seven provinces of Vietnam in 2021. Full-length PRRSV ORF5 genes from the 19 samples were amplified, sequenced, and compared to the corresponding sequences of referenced PRRSV strains from Genbank. The genetic analysis showed that 12 isolates were the highly pathogenic PRRSV subtype (HP-PRRSV) lineage 8, sublineage 8.7; six isolates were the classical North American PRRSV subtype (US-PRRSV), NADC-like group, lineage 1, sublineage 1.4, which were reported in Vietnam for the first time; and the final isolate was a vaccine-like strain. The field isolates of HP-PRRSV had relatively higher genetic diversity with US-PRRSV vaccine strains (84.0-94.5%) than HP-PRRSV vaccine strains (95.3-98.6%). Meanwhile, the six NADC-like isolates had low nucleotide similarity with US-PRRSV and HP-PRRSV vaccine strains (83.4-85.4% and 83.2-84.0%, respectively). Many amino acid substitutions were found in antigenic regions of GP5 involved in response to early antibody production, neutralizing antibodies, and viral immune evasion between these field strains and PRRSV vaccine strains. These findings provide insights into the molecular characteristics, genetic diversity, antigenicity, and evolution of PRRSV strains in Vietnam and postulate a compelling explanation for the limitations of current vaccination efforts.

In 2019, multiple FMD outbreaks occurred in swine farms vaccinated against FMDV in southern Vietnam. This study investigated the genotypic characteristics of FMDV strains from these outbreaks. Seven samples were collected from pigs exhibiting FMD clinical signs. All FMDV-positive samples were amplified and sequenced for the gene encoding the VP1. Results were analyzed and compared with sequences of reference strains and vaccine strains on GenBank. Phylogenetic analysis showed that all seven field isolates belonged to serotype O, topotype SEA/Mya-98. These strains shared high homology with strains from Vietnam (2018), Korea, and China, but low homology with vaccine strains. Moreover, 21 amino acid substitutions were found in the VP1 protein of the FMDV field strains, many of which were crucial antigenic determinants involved in the neutralization of FMDV. These findings suggest that the current vaccine may not be effective against the emerging FMDV strains in southern Vietnam.

Abstract Background Canine parvovirus type 2 (CPV‐2) is known as the primary etiological agent cause of acute gastroenteritis, myocarditis and death of canids worldwide. In Vietnam, although CPV‐2 infection and its outbreaks are the most important risk factors of the canine's health concern, lack of available information about the molecular epidemiology of the CPV‐2. Objectives In this study, the complete coding sequences of 10 CPV‐2 strains collected from dogs vaccinated with CPV‐2 vaccination were analysed to better understand the genomic characteristics of the current circulating CPV‐2 in Vietnam. Methods Ten CPV‐specific PCR‐positive rectal swab samples were collected from dogs with acute symptoms of haemorrhagic diarrhoea and vomiting in Vietnam in 2019. The complete coding sequences of these CPV strains were analysed to determine their phylogeny and genetic relationship with other available CPV strains globally. Results Analysis of the VP2 gene sequences demonstrated that the studied strains belonged to the new CPV‐2c variants with the unique mutations at amino acids 5 Ala‐Gly and 447 Iso‐Met . Phylogenetic tree analysis indicated that the studied strains share a common evolutionary origin with the current CPV‐2c strains circulating in dogs in Asia countries, including China, Thailand, Taiwan and Mongolia, in recent years. Low sequence identity between the studied strains and commercial vaccine strains was observed. Conclusions This study provides deep insights into the molecular characteristics, genetic diversity, and evolution of circulating CPV‐2 strains in Vietnam. We recommend more studies to estimate the effectiveness of the CPV vaccine and the need to continue developing other effective vaccination essential to better control the widespread of these new CPV‐2 variants.

Lung and brain development is often altered in infants born preterm and exposed to excess oxygen, and this can lead to impaired lung function and neurocognitive abilities later in life. Oxygen-derived reactive oxygen species and the ensuing inflammatory response are believed to be an underlying cause of disease because over-expression of some anti-oxidant enzymes is protective in animal models. For example, neurodevelopment is preserved in mice that ubiquitously express human extracellular superoxide dismutase (EC-SOD) under control of an actin promoter. Similarly, oxygen-dependent changes in lung development are attenuated in transgenic SftpcEC-SOD mice that over-express EC-SOD in pulmonary alveolar epithelial type II cells. But whether anti-oxidants targeted to the lung provide protection to other organs, such as the brain is not known. Here, we use transgenic SftpcEC-SOD mice to investigate whether lung-specific expression of EC-SOD also preserves neurodevelopment following exposure to neonatal hyperoxia. Wild type and SftpcEC-SOD transgenic mice were exposed to room air or 100% oxygen between postnatal days 0-4. At 8 weeks of age, we investigated neurocognitive function as defined by novel object recognition, pathologic changes in hippocampal neurons, and microglial cell activation. Neonatal hyperoxia impaired novel object recognition memory in adult female but not male mice. Behavioral deficits were associated with microglial activation, CA1 neuron nuclear contraction, and fiber sprouting within the hilus of the dentate gyrus (DG). Over-expression of EC-SOD in the lung preserved novel object recognition and reduced the observed changes in neuronal nuclear size and myelin basic protein fiber density. It had no effect on the extent of microglial activation in the hippocampus. These findings demonstrate pulmonary expression of EC-SOD preserves short-term memory in adult female mice exposed to neonatal hyperoxia, thus suggesting anti-oxidants designed to alleviate oxygen-induced lung disease such as in preterm infants may also be neuroprotective.

Background Systemic innate immune priming is a recognized sequela of post‐ischemic neuroinflammation and contributor to delayed neurodegeneration. Given mounting evidence linking acute stroke with reactive lung inflammation, we asked whether enhanced expression of the endogenous antioxidant extracellular superoxide dismutase 3 (SOD3) produced by alveolar type II pneumocytes would protect the lung from transient global cerebral ischemia and the brain from the delayed effects of ischemia‐reperfusion. Methods and Results Following 15 minutes of global cerebral ischemia or sham conditions, transgenic SOD3 and wild‐type mice were followed daily for changes in weight, core temperature, and neurological function. Three days after reperfusion, arterial and venous samples were collected for complete blood counts, flow cytometry, and SOD3 protein blotting, and immunohistochemistry was performed on lung and brain tissue to assess tissue injury, blood‐brain barrier permeability, and neutrophil transmigration. Relative to ischemic controls, transgenic SOD3 mice performed better on functional testing and exhibited reduced peripheral neutrophil activation, lung inflammation, and blood‐brain barrier leak. Once released from the lung, SOD3 was predominantly not cell associated and depleted in the venous phase of circulation. Conclusions In addition to reducing the local inflammatory response to cerebral ischemia, targeted enrichment of SOD3 within the lung confers distal neuroprotection against ischemia‐reperfusion injury. These data suggest that therapies geared toward enhancing adaptive lung‐neurovascular coupling may improve outcomes following acute stroke and cardiac arrest.

Immune-mediated reperfusion injury is a critical component of post-ischemic central nervous system (CNS) damage. In this context, the activation and recruitment of polymorphonuclear neutrophils (PMNs) to the CNS induces neurotoxicity in part through the release of degradative enzymes, cytokines, and reactive oxygen species. However, the extent to which close-range interactions between PMNs and neurons contribute to injury in this context has not been directly investigated. We devised a co-culture model to investigate mechanisms of PMN-dependent neurotoxicity. Specifically, we established the effect of PMN dose, co-incident neuronal ischemia, lipopolysaccharide (LPS)-induced PMN priming, and the requirement for cell-cell contact on cumulative neuron damage. Pre-exposure of day in vitro 10 primary cortical neurons to oxygen-glucose deprivation (OGD) enhanced PMN-dependent neuronal death. Likewise, LPS-induced priming of the PMN donor further increased PMN-induced toxicity in vitro compared to saline-injected controls. Compartmentalization of LPS-primed PMNs using net wells confirmed the requirement for close-range cell-cell interactions in the process of PMN-induced neuronal injury. Moreover, time-lapse imaging and quantitative neurite analyses implicate PMN-neurite interactions in this pathological response. These experiments establish a platform to investigate immune and neural factors that contribute to post-ischemic neurodegeneration. Ischemic and immune priming enhance neurotoxicity in PMN-neuronal co-cultures. Moreover, cell-cell contact and neurite destruction are prominent features in the observed mechanism of post-ischemic neuronal death.

Classical swine fever (CSF) is a highly contagious, devastating, and transboundary viral disease that afflicts swine industries worldwide. Immunization with vaccines is one of the most effective strategies for controlling this disease. However, shifts in the antigenicity and pathogenicity of novel evolving viral strains have the potential to evade vaccination. In this study, 352 samples from swines exhibiting fever, hemorrhages, lethargy, and diarrhea in different pig farms located in 9 provinces of Vietnam were collected. CSFV was identified even within farms that had been vaccinated against CSFV. Several farms had swine which had been co-infection with CSFV and other pathogens. Copies of the E2 gene of 21 samples were isolated, cloned, sequenced, analyzed, and compared with copies of E2 in four vaccine strains. We identified a total of 42 amino acid substitutions in this glycoprotein, including 11 positions that affect the antigenic properties of E2 and 7 positions that are associated with neutralizing epitopes. The E2 glycoprotein of CSFV strains circulating in Vietnam and vaccine strains differ in their antigenicity. These findings provide deep insights into the molecular characteristics, genetic diversity, pathogenicity, antigenicity, and evolution of CSFV strains in Vietnam. Understanding the pathogenicity, antigenicity, and evolution of circulating CSFV strains will provide avenues for developing new vaccines and efficient approaches to control this disease.

The COVID-19 pandemic has caused a tremendous burden on global healthcare systems, demanding a convenient and effective biomarker for severity prediction. Recent studies have reported a bidirectional relationship between COVID-19 severity and metabolic diseases, such as diabetes, suggesting that a diabetes-regulating gene may play a crucial role in controlling the disease. This study examines the potential of GRB10, a protein that negatively regulates insulin signals, as a biomarker for COVID-19 severity. Data from 126 blood samples of COVID-19 patients were analyzed to assess the relationship between GRB10 gene expression and the severity of COVID-19 pneumonia. The results demonstrate significantly higher levels of GRB10 gene expression in patients who were admitted to ICU and required mechanical ventilation. High expression of GRB10 was also shown to be a good indicator for COVID-19 severity, with high specificity and robust association with increased risk of respiratory support requirement. Additionally, GRB10 was found to be an independent predictor of complicated outcomes in COVID-19 patients. These findings support that GRB10 could serve as a strong and reliable biomarker for COVID-19 severity and contribute to our understanding of COVID-19 progression and its association with diabetes mellitus.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide, with complicated stages. The HCC patients almost never show clinical signs or symptoms until the cancer is in its advanced stages. Thus, discovering biomarkers for early detection of HCC is critical for enhancing therapeutic efficacy in HCC patients. In this study, clinical information and gene expression data were retrieved from the Gene Expression Omnibus and The Cancer Genome Atlas, consisting of 612 patients. Raw data were processed using the z-score method for normalization. Kaplan-Meier curves, Chi-square tests, and log-rank tests were performed using R packages to evaluate the prognostic value of DHRS1. We found that DHRS1 expression in HCC tumors was consistently and significantly lower than that in normal tissues. In addition, the expression of DHRS1 was significantly associated with serum alpha-fetoprotein level, tumor size, and staging systems. Most importantly, high DHRS1 expression was correlated with longer relapse-free survival, disease-free survival, and overall survival. In our multivariate analysis, DHRS1 expression was an independent predictor of mortality and tumor recurrence. We identified DHRS1 as a novel tumor-suppressor gene. Down-regulation of DHRS1 in HCC is associated with tumor development and poor clinical outcomes. In conclusion, DHRS1 is a promising biomarker for the early diagnosis and prognosis of HCC in the age of precision medicine.

While most individuals infected with COVID-19 recover completely within a few weeks, some continue to experience lingering symptoms. This study was conducted to identify and describe the clinical and subclinical manifestations of adult patients from the long-term effects of COVID-19.The study analyzed 205 medical records of inpatients (age ≥ 16 years, ≥ 4 weeks post-COVID-19 recovery, and a negative SARS-CoV-2 status at enrollment) at Thong Nhat Hospital, Vietnam, from 6 September 2021 to 26 August 2022, using R language software.The majority of patients hospitalized with long COVID-19 symptoms (92.68%) had normal consciousness. The most common symptoms on admission were fatigue (59.02%), dyspnea (52.68%), and cough (42.93%). In total, 80% of patients observed respiratory symptoms, primarily dyspnea, while 42.44% reported neurological symptoms, with sleep disturbance being the most common. Noticeably, 42.93% of patients experienced respiratory failure in the post-COVID-19 period, resembling acute respiratory distress syndrome.These findings provide crucial insights into the epidemiology, clinical, and subclinical aspects of post-COVID-19 conditions, shedding light on the prevalence of common symptoms and the demographic distribution of affected patients. Understanding these manifestations is vital for patient well-being, improved clinical practice, and targeted healthcare planning, potentially leading to better patient care, management, and future interventions.

Background: Depression is a widespread and incapacitating mental health disorder that impacts millions of people worldwide, playing a substantial role in the overall global health challenges. Depression has a big impact on a person’s quality of life, cognitive and social functioning, risk of suicide, risk of heart disease and other illnesses, as well as death from all causes. . Objective: Objective: It may be challenging to choose the best tools to screen for severe depression in patients with recurrent depression disorder (PRD) considering the diversity of psychological scales in Vietnam. The aim of this study was to evaluate diagnostic value for detect severe depression of four psychological scales including Hamilton Depression Rating Scale (HAM-D), Hamilton Anxiety Rating Scale (HAM-A), Beck Depression Inventory Scale (BECK), and Zung’s Self-Rating Anxiety Scale (SAS) by genders and age groups among PRD in Vietnam. Methods: This study was conducted at National Institute of Mental Health, Bach Mai Hospital, Vietnam, from 2020 to 2021. There were 109 PRD evaluated with HAM-D, HAM-A, BECK, and SAS by qualified psychiatrists. By analysing Area Under the Curve (AUC) of Receiver Operating Characteristic (ROC) curve, we determined sensitivity, specificity and cut points of four above scales.Results: Among four scales, the BECK scale had the best diagnostic effect with the most optimal sensitivity and specificity (61.64% and 75%, respectively). We proposed the new cut-off of HAM-D, HAM-A, BECK, and SAS for detecting severe depression among PRD were 20, 34, 30, and 45, respectively. By genders, the cut points for the HAM-D, HAM-A, BECK, and SAS in males were 20, 27, 34, and 44, respectively, while those figure in females were 14, 34, 30, and 46, respectively. By age groups, adults had cut values for four above scales of 20, 34, 27, and 45, respectively, whereas those for the elderly were 16, 17, 35, and 44, respectively. Conclusion: We highly recommended that BECK is the most optimal method to screen severe depression in PRD in Vietnam. It is essential to utilize varied cut values of HAM-D, HAM-A, BECK, and SAS for different genders and age groups.

Ung thư vú là loại ung thư phổ biến nhất ở phụ nữ, tuy nhiên nguyên nhân tử vong chính ở ung thư vú là do di căn vào các cơ quan khác trong cơ thể. Trong đó, phổi là một trong những đích đến chủ yếu của ung thư vú di căn. Việc xác định ung thư vú có di căn hay không sẽ giúp cho quá trình điều trị của bệnh nhân dễ dàng và đạt hiệu quả cao hơn. Do đó, việc phát triển một chỉ thị dự đoán khả năng di căn ở bệnh nhân ung thư vú sẽ cung cấp một giải pháp hữu hiệu giúp quá trình điều trị dễ dàng, nâng cao khả năng và thời gian sống của bệnh nhân. Trong nghiên cứu này, chúng tôi đã phân tích mối tương quan của Cilia and flagella-associated protein 410 (CFAP410) với việc di căn vào phổi ở bệnh nhân ung thư vú. Kết quả cho thấy những bệnh nhân ung thư vú không di căn vào phổi có mức độ biểu hiện CFAP410 cao hơn rõ rệt so với những bệnh nhân ung thư vú di căn phổi. Đồng thời, những bệnh nhân có mức độ biểu hiện CFAP410 cao có nguy cơ di căn thấp và thời gian sống của những bệnh nhân này cũng cao hơn rõ rệt so với những bệnh nhân có mức độ biểu hiện CFAP410 thấp. Nghiên cứu của chúng tôi cũng chỉ ra CFPAP410 có thể được sử dụng như một chỉ thị độc lập giúp hỗ trợ nhận biết ung thư vú di căn phổi sớm, để từ đó có phương pháp điều trị hiệu quả giúp những bệnh nhân ung thư vú di căn phổi có thể kéo dài thời gian sống.

Polyurethane (PU) foam is formed by the condensation of 2 components Polyol and Isocyanate. PU foam waste can be recycled by glycolysis which decomposes the polymer chains into polyol. The recycled polyol can then be used as the material to make new PU foam. However, the recycled Polyol is mixed with unprofitable primary and secondary amines, and it is not suitable for use as a raw material for the production of insulating foam because of its small average molecular weight, high hydroxyl index, etc. In this study, recycled Polyol will be modified with vegetable oil for the purpose of removing the amines mentioned above, creating the product with basic properties like commercial Polyol. Research results show that the regenerated Polyol after modification has the low hydroxyl index of 423.5 mg KOH/g and the viscosity of 4400 mPa.s, which are quite similar to that of commercial Polyol and the mass average molecular weight (2440.6) much higher than regenerated polyol.

Le dépistage de la carence en vitamine B12 (B12) a longtemps reposé sur le seul dosage sérique avec un seuil classique de 200 ng/L. Néanmoins, ce seuil apparaît peu sensible pour détecter précocement la carence. Les experts ont donc proposé un dépistage de la carence en B12 à l’aide de 2 marqueurs : acide méthylmalonique (MMA) (plasmatique ou urinaire) et homocystéïne (plasmatique) (Hcyst). En les utilisant, nous avons observé une prévalence de 23,3 % de carence en B12 chez 490 patients hospitalisés en médecine interne dans un travail précédent. Cette méthodologie plus sensible permet de dépister des carences moins sévères, généralement non liées à la maladie de Biermer et dont l’étiologie pose parfois question. Nous avons, dans ce travail, exploré l’hypothèse d’un lien entre carence en vitamine B12, metformine et inhibiteur de pompes à protons (IPP). Durant 15 semaines, les patients hospitalisés dans le service de médecine interne du CHU d’Angers et subissant un prélèvement sanguin ont eu une exploration de la carence en B12, sauf opposition après information éclairée (protocole MIB12). La carence était affirmée devant un taux sérique de B12 inférieur à 201 ng/L, ou devant un taux entre 201 et 350 ng/L si l’Hcyst était supérieure à 13 μmol/L chez les femmes et 15 μmol/L chez les hommes et/ou si le MMA urinaire était supérieur à 1,5 μmol/mmol de créatininurie. Dans ce travail, seuls les patients bénéficiant d’un traitement par metformine ou IPP depuis plus d’un an ont été inclus. Les patients sous metformine ont été comparés à l’ensemble de la population du protocole MIB12 en analyse univariée (Khi2) et multivariée (régression logistique). Concernant les patients sous IPP, devant de multiples facteurs confondants entre prise d’IPP et étiologies de carences en B12, nous avons comparé les patients sous IPP à ceux ne prenant pas d’IPP de même sexe, de même âge (±3 ans), après exclusion des autres causes de carence en B12 et des rares patients sous anti-H2. Parmi les 490 patients du protocole MIB12, d’âge médian de 67,5 ans [50–82], 114 (23,3 %) patients présentaient une carence en B12. Parmi la population totale, 26/490 (5,3 %) patients étaient traités depuis plus d’un an par metformine, dont 13 (50 %) présentent une carence en B12. L’utilisation de metformine seule représentait 11,4 % des étiologies de carence en B12. En analyse univariée, l’odd ratio (OR) de carence en B12 sous metformine est de 3,22 [IC95 % : 1,45–7,17] (p = 0,003). En analyse multivariée (variables du modèle : âge, sexe, maladie de Biermer, résection iléale, végétalisme, gastrite à Helicobacter pylori et prise d’IPP), l’OR de carence en B12 sous metformine est de 3,15 [IC95 % : 1,35–7,37] (p = 0,008). Nous avons extrait 84 patients sous IPP, sans autre étiologie potentielle de carence en B12, avec un âge médian de 76,5 ans [56,3–88] et les avons appariés à 84 patients ne prenant pas d’IPP, avec un âge médian de 76,5 ans [56–87]. Dans le groupe IPP, 19 (22,6 %) patients avaient une carence en B12 contre 8 (9,5 %) dans le groupe sans IPP (p = 0,02) avec un OR de 2,78 [IC95 % : 1,14–6,76]. Une méta-analyse a estimé à 10,7 % la prévalence de la carence en B12 chez des patients diabétiques sous metformine (OR 2,45 [IC95 % : 1,74–3,44]). Néanmoins, les méthodologies des études sélectionnées étaient très hétérogènes [1]. À notre connaissance, une seule étude a évalué les marqueurs MMA et Hcyst chez ces patients, mais ses conclusions sont discordantes avec le reste de la littérature, évoquant un phénomène de transfert de la B12 sous metformine du sang vers les cellules, responsable de « fausses » carences. Cette hypothèse est basée sur le constat d’une B12 érythrocytaire élevée sous metformine mais, du fait de l’absence de mitochondries et donc de métabolisme du MMA dans les globules rouges, ces cellules semblent peu représentatives du métabolisme intracellulaire global de la B12. Concernant les IPP, les données sont plus ténues et les prospectives rares. Une étude rétrospective sur 210 155 patients issus du système de santé américain met en évidence un OR de carence en B12 sous IPP (> 2 ans) de 1,65 [IC95 % : 1,58–1,73] avec un dépistage uniquement basé sur le taux sérique de B12 [2]. À notre connaissance, une seule autre étude a évalué l’impact des IPP au long cours sur la carence en B12, via l’Hcyst et le MMA, mais sa méthodologie ne permet pas de conclure [3]. Dans cette étude prospective, nous démontrons qu’un traitement prolongé (> 1 an) par metformine et IPP est associé significativement à la carence en B12, dépistée à l’aide des dosages de Hcyst et de MMA, chez des patients hospitalisés en médecine interne.

Abstract Background: Chemotherapy induced alopecia (CIA) is considered the most distressing side effect of chemotherapy for breast cancer patients. Scalp hypothermia offers hope to minimize chemotherapy induced alopecia (CIA) for breast cancer patients. We present data from a pilot study of scalp hypothermia with the Penguin Cold Cap System™ in patients receiving a combination chemotherapy regimen. Patients and Methods: Stage I-IIIC breast cancer patients, receiving adjuvant chemotherapy regimens with or without (A) were consented. Standard dose regimens included doxorubicin-cyclophosphamide (AC) x 4 cycles, dose dense, doxorubicin-cyclophosphamide followed by taxol (AC-T) x 8 cycles, taxotere-doxorubicin-cyclophosphamide (TAC) x 6 cycles, taxotere-cyclophosphamide (TC) x 4 cycles and taxotere-carboplatnium-trastuzumab (TCH) x 6 cycles. Photos were taken before and with each cycle and 3 weeks post chemotherapy, Dean's alopecia scale was used for grading. Caps were cooled to 8oC. Caps 1-2 were 20 minutes each prior to infusion, following caps were changed q 30 minutes throughout chemotherapy and for 3 hours post-chemotherapy. Results: See tables 1 and 2 for patient data. We enrolled 34 patients (22 (A) containing; 12 non (A) containing) after informed consent. Of patients withdrawn, 1 patient (AC-T) had metastatic disease at the time of registration and did not start scalp hypothermia,1 patient (TC) had scalp discoloration; 2 patients (AC and TAC) withdrew due to discomfort of cooling; 1 patient (TC) withdrew prior to start of therapy due to fear of discomfort and 1 patient (AC) was withdrawn for coloring hair at time of treatment. The mean percent of CIA in the (A) containing group was 52% (SD: 17 CI: 40-70) and the mean percent CIA in non (A) containing group was 25% (SD: 36 CI: 5-100). A comparison of the means yielded a p-value of 0.0003 in favor of non (A) containing regimens. Of the 12 patients in the non (A) containing regimen 83% (3 TCH, 7 TC) did not require a prostheses and of the patients receiving an (A) containing regimen 47% (8 AC) did not require a prostheses. For those patients who completed scalp hypothermia through chemotherapy, the median CIA for TC and TCH combined was 10% hair loss (5,25) and for AC, AC-T and TAC combined was 50% hair loss (45,70). Discussion: All patients who received TAC or AC-T had grade 4 CIA and needed a hair prostheses. Most AC patients preserved some of their hair. Hair thinning was even and not patchy in this group and most had no need for prostheses. Patients in the TC or TCH group, who were able to complete the scalp hypothermia therapy, retained 90% or better, of their hair and there was no need for prostheses in these groups. We found the scalp hypothermia technique used here reduces hair loss in AC patients and offers the possibility of CIA prevention for women with breast cancer receiving TC or TCH.Table 1. Data for all enrolled patientsRegimenEnrolledWithdrewCompletedAC1028AC-T716TAC514TC927TCH3-3 Table 2. Deans alopecia scale for all enrolled patientsRegimenGrade1 Excellent &amp;lt;25%Grade 2 Good 25-50%Grade 3 Moderate 50-75%Grade 4 Poor &amp;gt;75%AC2422AC-T---7TAC---5TC7--2TCH3--- Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5040.

Cerebral ischemia triggers a cascade of neuroinflammatory and peripheral immune responses that contribute to post-ischemic reperfusion injury. Prior work conducted in CNS ischemia models underscore the potential to harness non-antibiotic properties of tetracycline antibiotics for therapeutic benefit. In the present study, we explored the immunomodulatory effects of the tetracycline derivative 9-tert-butyl doxycycline (9-TB) in a mouse model of transient global ischemia that mimics immunologic aspects of the post-cardiac arrest syndrome. Pharmacokinetic studies performed in C57BL/6 mice demonstrate that within four hours after delivery, levels of 9-TB in the brain were 1.6 and 9.5-fold higher than those obtained using minocycline and doxycycline, respectively. Minocycline and 9-TB also dampened inflammation, measured by reduced TNFα-inducible, NF-κβ-dependent luciferase activity in a microglial reporter line. Notably, daily 9-TB treatment following ischemia-reperfusion injury in vivo induced the retention of polymorphonuclear neutrophils (PMNs) within the spleen while simultaneously biasing CNS PMNs towards an anti-inflammatory (CD11bLowYm1+) phenotype. These studies indicate that aside from exhibiting enhanced CNS delivery, 9-TB alters both the trafficking and polarization of PMNs in the context of CNS ischemia-reperfusion injury.

Background and ObjectivesStudies implicate the lung in moderating systemic immune activation via effects on circulating leukocytes. In this study, we investigated whether targeted expression of the antioxidant extracellular superoxide dismutase (SOD3) within the lung would influence post-ischemic peripheral neutrophil activation and CNS reperfusion injury.MethodsAdult, male mice expressing human SOD3 within type II pneumocytes were subjected to 15 min of transient global cerebral ischemia. Three days post-reperfusion, lung and brain tissue was collected and analyzed by immunohistochemistry for inflammation and injury markers. In vitro motility and neurotoxicity assays were conducted to ascertain the direct effects of hSOD3 on PMN activation. Results were compared against C57BL/6 age and sex-matched controls.ResultsRelative to wild-type controls, hSOD3 heterozygous mice exhibited a reduction in lung inflammation, blood-brain barrier damage, and post-ischemic neuronal injury within the hippocampus and cortex. PMNs harvested from hSOD3 mice were also resistant to LPS priming, slower-moving, and less toxic to primary neuronal cultures.ConclusionsConstitutive, focal expression of hSOD3 is neuroprotective in a model of global cerebral ischemia-reperfusion injury. The underlying mechanism of SOD3-dependent protection is attributable in part to effects on the activation state and toxic potential of circulating neutrophils. These results implicate lung-brain coupling as a determinant of cerebral ischemia-reperfusion injury and highlight post-stroke lung inflammation as a potential therapeutic target in acute ischemic cerebrovascular injuries.

La prévalence de la carence en vitamine B12 (B12) est estimée à 1 à 2 % de la population générale, jusqu’à 10 % chez les plus de 65 ans. Le seuil sérique de 200 ng/L, longtemps retenu pour le diagnostic, apparaît insuffisamment sensible. Plusieurs auteurs ont retenu l’homocystéïne et l’acide méthylmalonique, substrats des réactions impliquant la cobalamine [1], comme marqueurs intéressants pour un dépistage précoce lorsque le taux sérique est compris entre 201 et 350 ng/L. Nous nous sommes donc interrogés sur la fréquence de la carence en B12 au sein d’un service de médecine interne à l’aide de cette nouvelle méthodologie. Nous avons par ailleurs évalué la fréquence des carences en fer et en folates associées à la carence en B12. Durant 15 semaines, tous les patients hospitalisés dans le service de médecine interne et maladies vasculaires du CHU d’Angers et devant subir un prélèvement sanguin ont été inclus dans le protocole MIB12 sauf opposition après information éclairée. Tous les patients avaient un dosage sérique de B12, de folates sériques et érythrocytaires, de protéine C-réactive (CRP) et un bilan martial. Chez tous les patients ayant une B12 inférieure à 351 ng/L, étaient recueillies les données épidémiologiques, cliniques et biologiques simples. Chez les patients ayant un taux entre 201 et 350 ng/L étaient également dosées l’homocystéïnémie (Hcyst), avec un seuil de 13 μmol/L chez les femmes et 15 μmol/L chez les hommes, et la méthylmalonaturie (MMAu) avec un seuil de 1,5 μmol/mmol de créatininurie [2]. Les tests statistiques ont été réalisés à l’aide du logiciel Graphpad Prism v6.01. Parmi les 534 patients incluables, 492 ont pu être inclus, avec un âge médian de 67 ans [IC95 % : 50 ; 82]. Parmi ces derniers, 38 (7,7 %) présentaient une B12 supérieure à 1000 ng/L, 290 (58,9 %) une B12 comprise entre 351 et 1000 ng/L, 144 (29,3 %) une B12 entre 201 et 350 ng/L et 20 (4,1 %) une B12 inférieure à 201 ng/L. Parmi les 144 patients ayant un taux entre 201 et 350 ng/L, la carence était affirmée par l’Hcyst et/ou le MMAu chez 90 (62,5 %). Dans notre population, la carence en B12 concernait donc 110 (22,4 %) patients. La carence martiale (odds ratio [OR] : 1,935 ; IC95 % : 1,171 ; 3,198) et la carence en folates (OR : 2,441 ; IC95 % : 1,438 ; 4,144) étaient statistiquement associées à la carence en B12. L’hémoglobinémie médiane des patients carencés en B12 était statistiquement inférieure aux patients non carencés en B12, de 12,5 g/dL [10,8 ; 13,9] versus 13,3 g/dL [IC95 % : 12,1 ; 14,5] (p = 0,01). Une macrocytose (VGM > 98 fL) n’était notée que chez 16 (14,5 %) patients carencés en B12. Parmi les patients carencés, 52 (47,3 %) présentaient une hémoglobinémie inférieure à 12 g/dL, 36 (32,7 %) des signes neurologiques, 22 (20 %) des troubles cognitifs mal étiquetés, 24 (21,8 %) une glossite compatible avec une glossite de Hunter. Vingt-huit (25,5 %) patients paraissaient asymptomatiques. En utilisant l’algorithme de dépistage basé sur l’Hcyst et le MMAu, la prévalence de la carence en B12 dans notre population était de 22,4 %. Cette proportion importante est inhabituelle mais est comparable aux 17,2 % trouvés dans une étude récente concernant 14 904 patients âgés [3]. Néanmoins, notre population carencée en B12 comporte 20 (18,2 %) patients âgés de moins de 50 ans et un nombre important de patients atteints de maladies auto-immunes. Ainsi, nous nous interrogeons sur le lien entre carence en B12 et pathologies dysimmunitaires. Par ailleurs, nous avons pu mettre en évidence un lien statistique entre carences en B12, en folates et en fer, alors que le raisonnement habituel les oppose. L’association des carences en B12 et en fer remet en cause l’arbre diagnostique des anémies basé sur la macrocytose, d’autant plus que seuls 14,5 % des patients carencés en B12 présentaient une macrocytose. Cette étude montre que la carence en vitamine B12 est une problématique fréquente chez les patients hospitalisés en médecine interne. Le fait que 74,5 % des patients carencés présente des manifestations attribuables à la carence en B12 indique que son dépistage systématique pourrait être cliniquement pertinent.

Introduction: Cardiac arrest induces a robust systemic inflammatory response that exacerbates CNS injury and is characterized in part by neutrophil (PMN) migration to the brain. Tetracyclines have been shown to reduce inflammation after stroke, and here we test the effects of the tetracycline derivative 9-tert-butyl doxycycline (9TB) on PMN activation, trafficking, and ischemic neuroprotection in a mouse model of global ischemia-reperfusion. Hypothesis: Inhibition of PMN activation by 9TB will decrease PMN extravasation in the CNS and mitigate ischemia-reperfusion injury. Methods: Transient global cerebral ischemia was induced in LysM-EGFP mice by 3-vessel occlusion (3VO). Mice were given 50 μg/kg lipopolysaccharide (LPS) to simulate endotoxemia observed after cardiac arrest and daily injections of 25 mg/kg 9TB or vehicle control. Blood was collected 4 hours after 3VO/LPS for fluorescence-activated cell sorting (FACS) analysis of PMN activation. Brain and spleen immunohistochemistry were performed after 3 days to assess injury and PMN burden. Results: Expression of the PMN activation marker CD11b was increased 4 hours after 3VO/LPS compared to sham (mean fluorescence intensity = 55,516 vs. 6,537) and lower in 3VO/LPS animals treated with 9TB (MFI = 36,445). While sham-treated groups showed little PMN infiltration into the brain (7.5 PMN/mm2 ± 2.2 vs. 1.9 PMN/mm2 ± 1.3; NS), 9TB treatment of shams increased splenic PMN sequestration (81.4 ± 8.3 vs. 38.0 ± 7.5; p&lt;0.001). This effect was enhanced with 3VO/LPS (112.2 ± 8.9 vs. 37.3 ± 0.1; p&lt;0.0001). 3VO/LPS animals receiving 9TB exhibited lower cortical PMN counts (19.3 PMN/mm2 ± 13.6) compared to those receiving vehicle (46.5 PMN/mm2 ± 5.5; p&lt;0.05). Daily 9TB after 3VO/LPS also decreased cortical injury compared to vehicle-treated controls (9.7% ± 6.8 vs. 32.2% ± 6.4; p&lt;0.05) with no difference between sham groups (5.5% ± 0.9 vs. 6.8% ± 5.8; NS). PMN burden was positively correlated with neuronal injury (Pearson’s r=0.8621, p&lt;0.01). Conclusions: 9TB treatment rapidly inhibits PMN activation and reduces PMN migration and CNS injury when delivered acutely following cerebral ischemia-reperfusion. Future studies are required to link ischemic neuroprotection with the observed effects on PMN activity.

Patterns of antimicrobial resistance in EAEC and STEC isolated from humans in southern Vietnam. (XLSX 10 kb)

During the past decade, the world has come to be aware more of Turkey as a result of her ever-growing economy. Turkey is, to some extent, perceived as a rising economic power in the international arena. Turkey further also belongs to the group of upper middle-income countries as categorized by the World Bank classification with 10,410 USD GNI per capita in 2011 in current prices. With the same manner, in the most recent document called the European Commission 2012 Progress Report for Turkey, Turkish economic performance was evaluated as progressive towards the economic convergence with the EU with macroeconomic stabilization. This paper endeavors to examine whether a high degree of sustainable economic convergence has been achieved, whether the national legislation is compatible with the Treaty and whether Turkey has fulfilled the economic requirements to become an integral part of the Euro-zone. Sustainable growth path in Turkey is pursued in the sense that Turkish institutions and economic policies have sustainably improved and effective enough in order for the economy of the nation to cope with those of the EU’s member states. In other words, this paper seeks to answer the question whether Turkish economy is ready to join the EU providing that there have been some reforms and changes in the institutions so far in addition to the capability to response to external shocks such as global financial crisis. This study is an attempt to focus extensively on the economic imperatives of Turkey-EU relations under the circumstances created along with the aftermath of the European sovereign debt crisis since 2008. In line with the framework of the Maastricht criteria for a fruitful economic performance in lieu of competitive EU single market, this paper argues that recent economic development in Turkey has proved its success in meeting with those criteria. Moreover, with the evidence of the less severe impacts of global financial and economic crisis on Turkish economy, especially on the banking sector, Turkish institutions proved their effective precautionary policies ahead of the crisis. This paper, hence, also endeavors to evaluate Turkish monetary and fiscal policy responses to the global crisis to further conclude that Turkish economy is on its sustainable development path to be a comparable and competitive member in the European Union. Keywords: European Union, Turkish Economy, Maastricht Criteria, Sustainable Growth, Monetary Policy, Fiscal Policy, Global Crisis.

Lowered Mg++ stores in humans seem to be involved in the pathogenesis of essential hypertension. However, some antihypertensive drugs (e. g. in particular diuretics) can additionally decrease plasma or intracelluar Mg++ stores. In this context the role of the new antihypertensive renin inhibitor aliskiren has not been studied in detail. In our study, presented here, 8 essential hypertensive patíents were treated with the renin inhibitor aliskiren (Rasilez or Rasilez/HCT). In each patient plasma Mg++ concentrations were studied before and under therapy (4.2 +/-1.5 months). The results showed no significant difference in plasma Mg++ and K+ concentrations in essential hypertensives before and under treatment with aliskiren. The plasma Mg++ concentrations of 8 essential hypertensive patients before and under therapy with aliskiren was not found significantly different (0.92 +/-0.04 versus 0.91 +/- 0.05 mmol/l). There was a significant effect on lowering blood pressure in all patients (systolic blood pressure decreased from 149.3 +/- 4.4 to 138.3 +/- 3.2 mmHg, p < 0.05 / diastolic blood pressure decreased from 89.4 +/- 3.0 to 85.5 +/- 2.4 mmHg, p < 0.05). There was no correlation between plasma Mg++ and K+ concentrations and blood pressure values before and under aliskiren therapy. In addition serum creatinine levels were not found significant different before and under therapy with aliskiren in our study (0.9 +/- 0.1 versus 0.91 +/- 0.2 mg/dl, n. s.). In conclusion a therapy with aliskiren concerning Mg++ and K+ handling is safe and reduces blood pressure significantly, in addition renal function was stable in each patient in longterm therapy.

Abstract HCC is the fifth most common malignancy in the world. HCC generally arises in the context of chronic liver diseases, or other metabolic, dietary or toxic factors. Hypoxia is a critical microenvironment in hepatcarcinogenesis. It occurs in series of distinct steps that include tumor cell invasion and proliferation. The process of EMT required for liver cancer cell invasion is regulated by a family of E-box-binding transcription repressors, which include Snail and Slug. Protein N, the first discovered histone methylase, is an epigenetic enzyme playing important role in regulation of gene expression and function by removing mono- or dimethyl moieties from H3K4 and H3K9. However, the molecular mechanisms underlying these biological behaviors have not been completely elucidated. Here, we present the first evidence that expression of Protein N was transcriptionally induced by Hif1 under hypoxia condition. We also showed that the up-regulated Protein N enhanced HCC cell survival and sustained epigenetic homeostasis via activating Snail under hypoxic conditions in vitro/in vivo. Furthermore, we revealed that Protein N/Snail stimulated Hif1 expression by a positive feedback loop. Conclusively, we elicited that Protein N is an essential mediator in epigenetic aberrances of HCC (This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (NRF-2016R1D1A1B03933763)). Note: This abstract was not presented at the meeting. Citation Format: Yong Hwa Jo, Minh Nam Nguyen, Tae Gyu Choi, Sung Soo Kim. LSD1 stimulates cell survival and epigenetic homeostasis via snail in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5471. doi:10.1158/1538-7445.AM2017-5471

Acute ischemic stroke is one of the leading causes of morbidity and mortality in America and the leading cause of adult long-term disability. Strokes due to emergent large vessel occlusion (ELVO) often lead to significant disability; however, they also can be amenable to treatment with the potential for good functional outcome. Over a short period, the standard of treatment has evolved considerably, from supportive care to systemic therapy and now to targeted therapy. The role for mechanical thrombectomy had been debated for years, but in light of five back-to-back publications demonstrating its superiority, it is now considered standard of care in those patients who meet criteria. This article aims to introduce the reader to the progression of events leading to the current practice of endovascular embolectomy in ELVO.

Systemic inflammation and multi-organ failure represent two hallmarks of the Post Cardiac Arrest Syndrome (PCAS), and when present, are associated with severe neurological injury and often mortality. With the return of spontaneous circulation, ‘primed,’ neurotoxic neutrophils (PMNs) release degradative enzymes, cytokines, and reactive oxygen species that cause blood-brain-barrier dysfunction, tissue injury, and further PMN activation. In our pilot studies, we noted that remote cerebral ischemiareperfusion triggered the activation and accumulation PMNs in the lung. Evidence from the critical care literature also suggests that interactions with the pulmonary endothelium, among others, may regulate systemic PMN de-priming. These observations led us to propose the existence of immunological coupling between the lung and brain and to investigate whether systemic inflammation impairs this protective influence in the setting of ischemia-reperfusion. To test this, we developed a model of PCAS in mice by pairing transient global cerebral ischemia (achieved by three-vessel occlusion, 3VO) with the exposure to the prototypical endotoxin lipopolysaccharide (LPS) upon reperfusion. After establishing an intraperitoneal dose of LPS sufficient to produce serum levels observed in post-arrest patients, we found that combined 3VO/LPS treatment induced PMN activation, bloodbrain barrier compromise, microglial activation, and a doubling of PMN accumulation and injury in the cerebral cortex. The 3VO/LPS procedure also promoted PMN accumulation and edema in the lung, as well as the trafficking of PMNs to the non-ischemic kidney and liver. Studies have shown that targeted expression of the antioxidant extracellular superoxide dismutase (SOD3) from type II pneumocytes is sufficient to reduce oxidantinduce lung injury and inflammation in mice. To test whether focal manipulation of lung redox biology could exert similar effects in our model, we examined the effects of 3VO/LPS treatment in the Tg(SOD3) model. Our results indicate that increased SOD3 expression in the lung was protective against 3VO/LPS-induced lung edema, pulmonary PMN accumulation, microglial activation, cortical damage, and hippocampal apoptosis. SOD3 expression reduced the expression of CD11b on the surface of PMNs but had little effect on trafficking to the brain following 3VO/LPS. The protective effects of SOD3 were, however, limited in mice exposed to transient global ischemia alone. Our work highlights the importance of lung-brain coupling in ischemia-reperfusion injury and suggests that interventions targeting both PMN priming and redox changes that occur in the lung after ischemia-reperfusion may be valuable. These findings are particularly salient given the increased risk of stroke in patients with underlying lung disease and endothelial damage caused by smoking and other cardiovascular risk factors. Given its accessibility to pharmacological manipulation, our work suggests that targeting the lung with inhaled pharmacological…

1. LI J.-S., TANG Y., LI Z.-T., DING X.-R., LI Z., 2017, Study on the Optical Performance of Thin-Film Light-Emitting Diodes Using Fractal Micro-Roughness Surface Model, Applied Surface Science, 410, 60–69. Google Scholar

In the context that the world is increasingly paying attention to sustainable development, green supply chain management becomes the optimal solution to help balance the three effects of sustainability: economic, environmental, and social.This paper provides a research overview of sustainability performance and green supply chain management practices.Thence, the authors propose a research model on the impact of green supply chain management on the sustainability performance of small and medium enterprises in Vietnam.

Curcuma aromatica Salisb. is a precious medicinal herb with proven uses such as antibacterial, antioxidant, anti-inflammatory, anti-cancer abilities, etc. This study aims to evaluate the effects of extracts from the rhizome of C. aromatica Salisb. collected in Yen Bai province for antibacterial and antioxidant activities. The results showed that the ethanol extracts of C. aromaticaSalisb. had strong antibacterial activity against three strains Staphylococcus aureus VTCC12275, S. lentusATCC29070, and Escherichia coli VTCC12272. The minimum inhibitory concentration (MIC) of the ethanol extracts of C. aromatica Salisb. against the three strains achieved 7, 6, and 9 μl/ml, respectively. Besides that, the extracts also proved antioxidant activity by the ability to scavenge free radicals (IC50). The initial findings suggested that C. aromatica Salisb. was a potential medicinal herb of Vietnam for developing medicinal products.

Giám sát tác nhân vi rút gây bệnh ở người trong nước thải là mô hình giám sát sức khỏe cộng đồng chủ động được nhiều quốc gia áp dụng. Tại Việt Nam, chưa có công bố nào về giám sát các vi rút gây bệnh trong nước thải. Dựa vào chương trình giám sát vi rút polio trong nước thải được triển khai tại Hà Nội từ tháng 11/2020, nghiên cứu này nhằm mục tiêu xác định sự có mặt của một số vi rút gây bệnh khác. 53 mẫu nước thải chưa qua xử lý được thu thập từ hai trạm xử lý và bốn cống gom nước thải sinh hoạt ở các sông tại Hà Nội, giai đoạn 11/2020 – 12/2021. Mẫu nước được cô đặc theo phương pháp 2-pha Dextran PEG và sau đó xét nghiệm phát hiện vi rút đường ruột (VRĐR), rota, noro và adeno. VRĐR phân lập được trên 6 (11,32%) mẫu, bao gồm echo 3, 6 và 11, mỗi type 2 mẫu. Vi rút rota, noro GI, noro GII và adeno lần lượt phát hiện trên 24 (45,28%), 16 (30,18%), 27 (50,94%) và 33 (62,26%) mẫu. Kết quả bước đầu cho thấy tính khả thi trong việc kết hợp song song giám sát vi rút polio với giám sát các vi rút gây bệnh khác trong môi trường nước thải, đặc biệt đối với vi rút noro và adeno mà hệ thống giám sát dựa trên bệnh nhân chưa được thực hiện tại Việt Nam.

Bệnh dịch tả heo cổ điển (Classical swine fever disease) là một bệnh lâu đời, nguy hiểm và gây thiệt hại kinh tế đáng kể cho ngành chăn nuôi heo trên toàn thế giới. Trình tự gene mã hóa protein E2 là một cơ sở quan trọng để đánh giá, so sánh đa dạng di truyền của CSFV và phát triển vaccine. Nghiên cứu này được tiến hành nhằm tạo ra các dòng E. coli mang plasmid chứa đầy đủ trình tự gene E2. 21 mẫu dương tính với CSFV đã được thu thập được biến nạp vào các dòng E. coli DH5α. Các plasmid sau đó được tinh sạch và giải trình tự nhằm đánh giá hiệu quả của phương pháp tạo dòng. Kết quả cho thấy nghiên cứu đã tạo thành công 21 dòng vi khuẩn E. coli mang toàn bộ gene E2 của CSFV. Các trình tự này tương đồng cao (87,94 – 98,84%) khi so sánh với 100 trình tự có độ tương đồng cao nhất trên NCBI. Ngoài ra, 19 trình tự tương đồng rất cao với các chủng thuộc phân nhóm 2.1c (95,00 – 96,34%) và 2 trình tự với phân nhóm 2.2 (92,05 – 93,03%). Nghiên cứu này là cơ sở cho việc áp dụng kĩ thuật tạo dòng E. coli mang gene E2 trong việc phân tích di truyền của CSFV một cách ổn định, cũng là cơ sở cho sự tạo ra các protein E2 tái tổ hợp phục vụ việc phát triển vaccine tiểu đơn vị chống CSFV sau này.

The landscape of orthopedic oncology is rapidly changing. These changes have been prompted by the stagnation of outcomes in the treatment of bone and soft tissue sarcomas, paving the way for molecular and immunologic treatment options in the management of these malignancies. Immuno-oncologic therapy or immunotherapy has led to improved outcomes for patients with cancer. Immunotherapy involves activating the immune system and an individual’s immune system to combat malignant cells. This method is effective because cancer cells proliferate by evading the immune system while they enlarge and spread to distant sites. Immunotherapy focuses on these methods of evasions, and interrupts these pathways. Prevention of the evasion of a host immune surveillance by the cancel cells inevitably leads to an active immune response against the tumor, decreased tumor burden, improved outcomes or cure. The comprehension of the underlying mechanisms associated with immune therapy is paramount, and an asset to the orthopedist in the treatment of cancer. This understanding will help provide comprehensive care for our patients in this era of precision medicine.

Introduction: Tissue damage and neuroinflammatory responses associated with cerebral ischemia trigger a systemic immune response that exacerbates brain injury during reperfusion and adversely influences functional recovery. Polymorphonuclear neutrophils (PMNs) are the first-line response to inflammation following acute brain injury, and evidence implicates lung-dependent PMN depriming as a critical endogenous protective mechanism against reperfusion injury. Methods: We explored mechanisms of PMN priming and neurotoxicity with in vivo modeling of systemic inflammation after brain ischemia-reperfusion as well as cellular culture experiments. Using transgenic mice overexpressing the human antioxidant gene superoxide dismutase 3 in the lung (TgSOD3), we tested the hypothesis that manipulation of the lung’s redox environment could mitigate PMN activation and post-ischemic brain injury. Injury was induced by occlusion of the common carotid and basilar arteries followed by reperfusion and lipopolysaccharide-induced systemic inflammation. To assess cell interactions using live microscopy, we cultured primary cortical neurons after oxygen-glucose deprivation (OGD) with primed PMNs from wild-type or TgSOD3 mice. Results: Our results show that pulmonary SOD3 protects against peripheral PMN activation, lung injury, brain injury, and neuroinflammation after ischemia/reperfusion with systemic inflammation. We also found that PMNs from TgSOD3 mice are less toxic to post-OGD cultures compared to wild-type PMNs. Our data indicate that direct cell-cell contact is required for PMN-dependent neurotoxicity in mixed cellular cultures and that pre-exposure of neurons to OGD amplifies this response. Analyses reveal that PMNs effect a considerable degree of neuritic damage in vitro , while in vivo modeling demonstrates cortical injury, blood-brain barrier compromise, PMN activation, and lung injury after reperfusion. Conclusion: Collectively, these studies expand our understanding of PMN-dependent mechanisms in post-ischemic toxicity, both directly on neurons and via effects on CNS inflammation, and argue that the inflammatory milieu within the lung may modulate CNS reperfusion injury via manipulation of peripheral PMN priming.

The unexpected tendency of amines and functionalized hydrazines to reduce the ethyl 3-phenylquinoxaline-2-carboxylate 1,4-di-N-oxide (1) to a quinoxaline (1c) and mono-oxide quinoxalines (1a and 1b) is described. The experimental conditions were standardized in the use of 2 equivalents of amine in ethanol under reflux for 2 hours, with the aim of studying the distinct reductive profile of the amines and the chemoselectivity of the process. With the exception of hydrazine hydrate, which reduced compound 1 to a 3- phenyl-2-quinoxalinecarbohydrazide derivative, the amines only acted as reducing agents.

In vitro generation of human peripheral sensory neurons may provide a framework for novel drug screening platforms and disease models of touch and pain. However, derivation of a functionally pure sensory neuron population remains a major unmet challenge. We discovered that, by expressing the transcription factors NGN2 and BRN3A, human pluripotent stem cells can be induced to differentiate into a surprisingly homogenous culture of cold- and mechano-sensing neurons. Although such a neuronal subtype has not been reported in mice, we found molecular evidence of its existence in adult human sensory ganglia. Combining NGN2 and BRN3A programming with neural crest patterning, we produced two additional populations of sensory neurons, including a more specialized mechanosensory neuron subtype. Finally, we applied this system to model a rare inherited sensory disorder, characterized by profound impairment of touch sensation and proprioception, caused by inactivating mutations in PIEZO2. Together these findings establish an approach to specify distinct sensory neuron subtypes in vitro, underscoring the utility of stem cell technology to capture human-specific features of physiology and disease.

This proceeding contains the papers that were presented at the 2nd International conference on Multimedia Analysis and Pattern Recognition (MAPR 2019) which was held in Ho Chi Minh City, Vietnam, from May 9th -10th, 2019.The main objective of the MAPR conferences is to bring together researchers and practitioners from both academia and industry for sharing their latest research findings, experimental results and consolidating potential collaborations on pattern recognition, multimedia analysis and related areas.The international program committee has accepted 16 full papers (acceptance rate of 57%) according to the reviewer's decision and comments within a scientific double-blinded review process.

Abstract Background We recently demonstrated the presence of the bacterial pathogen, Porphyromonas gingivalis ( Pg ), and its protease virulence factors, known as gingipains, in greater than 90% of AD brains. Brain gingipain levels significantly correlated with AD diagnosis and tau and ubiquitin pathology. Mechanistic studies in wild type mice demonstrated that Pg invades the brain after infection of the oral cavity, resulting in the development of neuropathology consistent with that of AD. These effects were blocked in mice after oral administration of the gingipain inhibitor COR388. In addition to neuropathology, AD is often accompanied by the comorbidity of cardiovascular disease. Pg has been linked to the development of atherosclerosis and the bacteria are found abundant within atheromatous plaque. We investigated if COR388 was efficacious in treating Pg‐ accelerated atherosclerosis in a rabbit model. Method Eighteen New Zealand White rabbits on a 13‐week regimen of 0.5% cholesterol diet to induce atherosclerosis were randomized in the study. Twelve rabbits were orally infected with Pg 3x/week for 6 weeks for oral disease induction and 6 rabbits were sham‐infected. Six Pg – infected rabbits were orally administered COR388 10mg/kg once daily for the entire 13 weeks of the study (prevention protocol), and 6 Pg‐ infected rabbits received vehicle for 13 weeks. Six sham‐infected rabbits received vehicle for 13 weeks. At 13 weeks, atherosclerotic plaques were quantified by assessing Sudan IV staining, histology, and ex vivo MRI. Serum levels of C‐reactive protein (CRP) were evaluated as a measure of systemic inflammation. Result Pg‐infected rabbits exhibited accelerated atherosclerotic disease severity than sham‐infected animals. COR388 diminished this atherogenesis compared to vehicle controls as evidenced by significantly less arterial plaque and a lower intima/media ratio. COR388 treatment also significantly reduced systemic levels of CRP. Conclusion COR388, a novel lysine‐gingipain inhibitor, is currently being tested in a Phase 2/3 clinical trial to target Pg for the treatment of AD. Based on the current preclinical data reported here, COR388 has the potential to attenuate atheroma formation and systemic inflammation in Pg‐ induced atherosclerosis and therefore may have beneficial effects on comorbid cardiovascular disease in Pg‐ associated AD.

A decrease in total magnesium content is not a direct proof of a decreased magnesium ion concentration. It could reflect a phosphate alteration or an ATP metabolism disorder. Plasma phosphate levels are lower in spontaneously hypertensive rats (SHRs) than in Wistar-Kyoto rats (WKYs), and defects in membrane regulation or mitochondrial ATP synthase occur. Only sparse data exist concerning cellular magnesium and phosphate concentrations in hypertensive cells. In aortic smooth muscle cells from 10 SHRs of the Münster strain and 10 age-matched normotensive WKY rats, the intracellular phosphate and magnesium content was measured by electron probe X-ray microanalysis (Camscan CS 24 apparatus, Cambridge, U.K.). The Mg++ content was 0.09 +/- 0.15 g/kg dry weight in SHRs versus 1.15 +/- 0.10 g/kg dry weight in WKY rats (p < 0.01). Vascular smooth muscle phosphate content was 23.6 +/- 0.79 g/kg dry weight in WKY rats versus 15.81 +/- 1.22 g/kg dry weight in SHRs (p < 0.01). In aortic smooth muscle cells of one month old SHRs intracellular magnesium was measured as 1.05 +/- 0.08 versus 1.09 +/- 0.09 g/kg dry weight in WKYs. Intracellular phosphate concentration in one month old SHRs was 18.71 +/- 2.41 versus 21.36 +/- 1.25 g/kg dry weight in WKYs (eight animals in each group). Aortic smooth muscle cells of SHRs are caracterized by markedly lowered intracellular phosphate and magnesium concentrations, resulting in an altered ATP-metabolism, as described earlier. Possibly a membrane defect or a magnesium deficiency or disturbed magnesium channels are responsible for the early onset in the pathogenesis of primary hypertension.

In the present study, authors propagated Sophora tonkinensisGagnep plants using stem nodal culture. The results indicated that on MS medium supplemented with 30 g/l sucrose, 5.5 g/l agar, 200 ml/l coconut water, 1 g/l activated charcoal, 0.75 mg/l TDZ shoots proliferated from stem segments have the best count and height of shoots. The most appropriate medium for multiplication of shoots was the MS medium supplemented with 30 g/l sucrose, 5.5 g/l agar, 200 ml/l coconut water, 1 g/l activated charcoal, 0.75 mg/l TDZ, 0.5 mg/l IBA, 2.0 g/l peptone, 30 g/l carrot puree, pH 5.5 with the results of 20.60 shoots/explant, shoot height of 3.75 cm and 4.6 leaves/shoot after 8 weeks of culture. Root formation of shoots carried out on the MS medium supplemented with 30 g/l sucrose, 5.5 g/l agar, 200 ml/l coconut water, 1 g/l activated charcoal, 1.0 mg/l αNAA gave the best result. In the nursery, a mixture of humus + coconut fiber powder (70:30 ratio) was regarded as the best substrate due to the high survival rate of plantlets (92%) and healthy plantlets (10.30 cm high with 7.2 leaves and 4.3 new roots/a plantlet) at 10 weeks after planting