Background
The environmental oxygen tension has been reported to impact the blastocyst quality and cell numbers in the inner cell mass (ICM) during human and murine embryogenesis. While the molecular ...mechanisms leading to increased ICM cell numbers and pluripotency gene expression under hypoxia have been deciphered, it remains unknown which regulatory pathways caused the underweight fetal body and overweight placenta after maternal exposure to hyperbaric oxygen (HBO).
Results
The blastocysts from the HBO‐exposed pregnant mice revealed significantly increased signals of reactive oxygen species (ROS) and nuclear Nrf2 staining, decreased Nf2 and Oct4 expression, increased nuclear Tp53bp1 and active caspase‐3 staining, and ectopic nuclear signals of Cdx2, Yap, and the Notch1 intracellular domain (N1ICD) in the ICM. In the ICM of the HBO‐exposed blastocysts, both Nf2 cDNA microinjection and Nrf2 shRNA microinjection significantly decreased the ectopic nuclear expression of Cdx2, Tp53bp1, and Yap whereas increased Oct4 expression, while Nrf2 shRNA microinjection also significantly decreased Notch1 mRNA levels and nuclear expression of N1ICD and active caspase‐3.
Conclusion
We show for the first time that maternal exposure to HBO at the preimplantation stage induces apoptosis and impairs ICM cell specification via upregulating Nrf2‐Notch1‐Cdx2 expression and downregulating Nf2‐Oct4 expression.
Key Findings
Compared to the blastocysts derived from normoxia‐exposed female mice, the blastocysts from hyperbaric oxygen (HBO)‐exposed mothers exhibited significantly increased levels of reactive oxygen species (ROS) and nuclear Nrf2 staining, along with significantly decreased membranous Nf2 staining throughout the entire embryo in immunofluorescence analyses. Additionally, there was a significant decrease in Oct4 expression, increased nuclear staining of Tp53bp1 and active caspase‐3, and ectopic expression of Cdx2, Yap, and the Notch1 intracellular domain (N1ICD) specifically within the inner cell mass (ICM).
Both microinjections of Nf2 overexpressor cDNA and Nrf2 shRNA into the pronuclear zygotes followed by oviduct transfer before daily HBO exposures significantly decreased the nuclear expression of Cdx2, Tp53bp1 and Yap whereas increased Oct4 expression in the ICM of the HBO‐exposed blastocysts.
Microinjection of Nrf2 shRNA into the pronuclear zygotes before daily HBO exposures significantly decreased Notch1 mRNA levels and nuclear expression of ectopic N1ICD and active caspase‐3 in the ICM of the HBO‐exposed blastocysts.
Microinjection of Nf2 overexpressor cDNA into the pronuclear zygotes before HBO exposure did not affect the levels of cell apoptosis, Notch1 mRNA and ectopic N1ICD expression in the ICM of the HBO‐exposed blastocysts.
An increasing incidence of Acute Myeloid Leukaemia (AML) has been reported in several Western countries. However, the epidemiology of AML in Asia is very limited. According to the National ...Comprehensive Cancer Network (NCCN) guideline of AML, a range of conventional therapy options is available to AML patients. Nevertheless, different treatment strategies may result in diverse healthcare utilization and costs. Understanding the treatment patterns, healthcare utilization and costs of AML would thus be essential for clinicians and policymakers to optimize the treatment strategies of AML.
The objective of this study was to investigate the incidence, treatment patterns, healthcare utilization and costs of AML in Taiwan using a nationwide population database.
We retrospectively identified AML patients diagnosed from 2006 to 2015 from the Taiwan Cancer Registry Database (TCRD) and estimated the epidemiology of AML in Taiwan. The TCRD was linked to National Health Insurance Research Database (NHIRD) to collect the treatment patterns and health care utilization. Patients diagnosed with AML from 2011 to 2015 were further identified to analyze treatment patterns, healthcare utilization and costs.
The crude annual incidence of AML increased from 2.78 to 3.21 cases per 100,000 individuals from 2006 to 2015. However, the age-standardized rate (ASRs) of AML slightly declined from 2.47 to 2.41 cases per 100,000 individuals in the same period. Among 2,179 AML patients who received induction therapy (median age: 56 years), most of them (n = 1744; 80.04%) received standard-dose cytarabine (SDAC) regimen. The remaining 162 patients received high dose cytarabine (HDAC) and 273 patients received non-standard dose cytarabine (N-SDAC) regimen as the induction therapy. The median medical costs in our study for patients treated with chemotherapy alone was $42,271 for HDAC, $36,199 for SDAC and $36,250 for N-SDAC. For those who received hematopoietic stem cell transplantation (HSCT) after induction therapy, their median medical costs were $78,876 for HDAC, $78,593 for SDAC and $79,776 for N-SDAC.
This study is the first population-based study conducted in Asia to provide updated and comprehensive information on epidemiology, treatment patterns and healthcare resource utilization and costs of AML.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
ObjectivesTo describe the occurrence of recurrent atherosclerotic cardiovascular disease (ASCVD) events within 3 years after a new-onset event, the associated disease burden and statin prescribing in ...patients with ASCVD in Taiwan.DesignRetrospective cohort study.SettingThis was a retrospective cohort study using Taiwan’s National Health Insurance Research Database.ParticipantsIn total, 111 399, 133 538 and 21 572 patients who were hospitalised with diagnosis of coronary heart disease (CHD), cerebrovascular disease (CBVD) and peripheral artery disease (PAD), respectively, between 1 January 2012 and 31 December 2014.Primary and secondary outcome measuresFor each index and recurrent event, patients were observed for 12 months after admission to quantify risks of mortality, recurrent events, statin treatment and healthcare use.ResultsWe identified 97 321, 120 914 and 14 794 patients with new-onset CHD, CBVD and PAD, respectively. The proportions of developing first, second and third recurrent events were 22.5%, 25.6% and 30.9% for CHD; 20.9%, 26.2% and 32.4% for CBVD and 40.2%, 41.4% and 43.6% for PAD, respectively. Most patients had the same type of ASCVD for their recurrent events as their new-onset event. The mortality rates increased with each recurrent event (p<0.05 for all three ASCVD groups). The rates of hospital readmission and emergency room (ER) visit increased with increasing recurrent events. For example, in the CHD group, the 1-year readmission rates following the index, first and second recurrent events were 43.1%, 47.6% and 55.3%, respectively, and the proportions of visiting ER were 46.4%, 51.9% and 57.8%, respectively. Statin prescribing was suboptimal at time of index event and recurrent events.ConclusionRecurrent ASCVD events were associated with a higher risk of recurrent event and mortality and greater healthcare use. However, statin prescriptions at index event and after each recurrent event were suboptimal.
•We provide a novel animal model of NMO by intrathecal injection of NMO-IgG into EAE mice.•This animal model closely recapitulates human NMO pathology with relevant clinical severity.•The results ...imply that NMO-IgG is a key role of the immune response and clinical severity of NMO.
Neuromyelitis optica (NMO) is recognized as a different CNS autoimmune disease from multiple sclerosis (MS). Whether NMO-IgG contributes directly to the pathogenesis of NMO or is just a serologic marker of autoimmune responses of the disease needs to be clarified. We created MOG-induced experimental autoimmune encephalomyelitis (EAE) mice by passively transferring NMO-IgG to model the pathogenic findings in NMO patients. The mice were divided into three groups and administered intrathecal PBS, human complement with IgG from normal subjects, or IgG from AQP4(+) patients on days 8 and 11 after immunization. The EAE scores of EAE mice with intrathecal NMO-IgG injection were significantly elevated 14 days post-immunization. All of the mice were sacrificed for brain and spinal cord pathology analysis on day 21 post-immunization. Compared to mice given normal human IgG, EAE mice injected with NMO-IgG had markedly decreased AQP4 and glial fibrillary acidic protein (GFAP) expression and fluorescent intensity in the brain and spinal cord but more scattered deposition of complement (C9neo). Thus, our studies not only support the pathogenic role of NMO-IgG with complement in NMO disease but also provide a platform for the development of future therapeutics.
Previous studies have shown that the experimental models of hypoxia-reoxygenation (H/R) mimics the physiological conditions of ischemia-reperfusion and induce oxidative stress and injury in various ...types of organs, tissues, and cells, both
in vivo
and
in vitro
, including human lung adenocarcinoma epithelial cells. Nonetheless, it had not been reported whether H/R affected proliferation, apoptosis, and expression of stem/progenitor cell markers in the bronchial epithelial cells. In this study, we investigated differential effects of consecutive hypoxia and intermittent 24/24-h cycles of H/R on human bronchial epithelial (HBE) cells derived from the same-race and age-matched healthy subjects (i.e., NHBE) and subjects with chronic obstructive pulmonary disease (COPD) (i.e., DHBE). To analyze gene/protein expression during differentiation, both the NHBE and DHBE cells at the 2nd passage were cultured at the air-liquid interface (ALI) in the differentiation medium under normoxia for 3 days, followed by either culturing under hypoxia (1% O
2
) for consecutively 9 days and then returning to normoxia for another 9 days, or culturing under 24/24-h cycles of H/R (i.e., 24 h of 1% O
2
followed by 24 h of 21% O
2
, repetitively) for 18 days in total, so that all differentiating HBE cells were exposed to hypoxia for a total of 9 days. In both the normal and diseased HBE cells, intermittent H/R significantly increased
HIF1A
,
BMP4
,
NOTCH1
,
MKI67
,
OCT4
, and
MUC5AC
expression, while consecutive hypoxia significantly decreased
NKX2-1
,
NOTCH3
,
HEY1
,
CC10
, and
FOXJ1
expression. Inhibition of
HIF1A
or
NKX2-1
expression by siRNA transfection respectively decreased
BMP4
/
NOTCH1
/
MKI67
/
OCT4
/
MUC5AC
and
NOTCH3
/
HEY1/CC10/FOXJ1
expression in the HBE cells cultured under intermittent H/R to the same levels under normoxia. Overexpression of
NKX2-1
via cDNA transfection caused more than 2.8-fold increases in
NOTCH3
,
HEY1
, and
FOXJ1
mRNA levels in the HBE cells cultured under consecutive hypoxia compared to the levels under normoxia. Taken together, our results show for the first time that consecutive hypoxia decreased expression of the co-regulated gene module
NOTCH3/HEY1/CC10
and the ciliogenesis-inducing transcription factor gene
FOXJ1
via
NKX2-1
mRNA downregulation, while intermittent H/R increased expression of the co-regulated gene module
BMP4/NOTCH1/MKI67/OCT4
and the predominant airway mucin gene
MUC5AC
via
HIF1A
mRNA upregulation.
The authors consider the problem of robust output estimation in the discrete-time setting. The uncertainty in the system is characterised by integral quadratic constraints with dynamic multipliers. ...The main technical contribution of this study is to derive two different synthesis conditions in terms of linear matrix inequalities (LMI) by two different approaches. The LMI condition derived by the first approach allows one to find the robust estimator and the performance certificate simultaneously, whereas the condition by the second approach has a smaller size but requires an additional step for recovering the estimator. The synthesis conditions are validated by numerical examples. The results verify the equivalence of the two approaches and show that the two-step approach is in fact computationally favourable when the system has large number of state variables.
Background: The presence of interdental papillae in the maxillary anterior region plays a key esthetic role. The aim of this study is to investigate the impact of demographic variables, such as ...gender and ages, and radiographic measurements of interdental area anatomy on the presence of interdental papillae.
Methods: Periapical radiographs of 102 interdental papillae between maxillary anterior teeth were obtained in 30 adults who had fully erupted permanent dentition, healthy gingiva, and well‐aligned maxillary anterior teeth. A radiopaque material was placed on the tip of the interdental papilla and the mucogingival junction. Radiographic measurements of tooth shape, alveolar bone level, and interdental space anatomy were undertaken using computer software.
Results: When each factor was evaluated individually, the shorter the distance between the contact bone and alveolar bone crest, the shorter the distance between two adjacent teeth, and the smaller the embrasure area, the more likely interdental papillae were present. Interdental papillae were more likely to be present between teeth with a rectangular tooth form. When all factors were evaluated together, the presence of interdental papillae was only significantly related to the distance from the contact point to the bone crest (P = 0.038).
Conclusion: In the anterior maxillary region, the shorter the distance between the contact point to the bone crest, the more likely interdental papillae were present.
Stress-induced hyperglycemia (SIH) is associated with poor functional recovery and high mortality in patients with acute ischemic stroke (AIS). However, intensive controlling of blood glucose by ...using insulin was not beneficial in patients with AIS and acute hyperglycemia. This study investigated the therapeutic effects of the overexpression of glyoxalase I (GLO1), a detoxifying enzyme of glycotoxins, on acute hyperglycemia–aggravated ischemic brain injury. In the present study, adeno-associated viral (AAV)-mediated GLO1 overexpression reduced infarct volume and edema level but did not improve neurofunctional recovery in the mice with middle cerebral artery occlusion (MCAO). AAV-GLO1 infection significantly enhanced neurofunctional recovery in the MCAO mice with acute hyperglycemia but not in the mice with normoglycemia. Methylglyoxal (MG)-modified proteins expression significantly increased in the ipsilateral cortex of the MCAO mice with acute hyperglycemia. AAV-GLO1 infection attenuated the induction of MG-modified proteins, ER stress formation, and caspase 3/7 activation in MG-treated Neuro-2A cells, and reductions in synaptic plasticity and microglial activation were mitigated in the injured cortex of the MCAO mice with acute hyperglycemia. Treatment with ketotifen, a potent GLO1 stimulator, after surgery, alleviated neurofunctional deficits and ischemic brain damage in the MCAO mice with acute hyperglycemia. Altogether, our data substantiate that, in ischemic brain injury, GLO1 overexpression can alleviate pathologic alterations caused by acute hyperglycemia. Upregulation of GLO1 may be a therapeutic strategy for alleviating SIH-aggravated poor functional outcomes in patients with AIS.
Grouper, Epinephelus coioides, fed a diet containing sodium alginate at 0 (control, named C) and 1.0 g kg−1 (named S) at a temperature of 28 °C for 12 days, were then further individually transferred ...to 28 (two groups named C-28 and S-28) or 20 °C (two groups named C-20 and S-20), and immune parameters and stress indexes were measured at the beginning and after 6, 12, 24 and 48 h of exposure. Examination of immune parameters revealed that the alternative complement activity (ACH50), lysozyme activity, phagocytic activity, superoxide dismutase, and respiratory bursts significantly increased in groupers fed the sodium alginate-containing diet for 12 days, and were higher in the S-28 than those of the C-28 and S-20 groups, which were higher than those of the C-20 group from 6 to 48 h except for ACH50 at 48 h, respiratory bursts at 48 h, and lysozymes at 6 h. For the assessment of stress indicators, cortisol, glucose, and lactate levels of serum significantly decreased in grouper fed the sodium alginate-containing diet for 12 days, and were higher in the C-20 group than those of the C-28 and S-20 groups, which were higher than those of the S-20 group at 6–48 h. In another experiment, grouper fed the test diet for 12 days at a temperature of 28 °C were challenged with Photobacterium damselae subsp. piscicida at a dose of 5 × 103 colony-forming units (cfu) (g fish)−1, and then individually transferred to 28 or 20 °C. The survival rate of challenged fish of the C-28 group was significantly lower than those of challenged fish of the C-20 and S-28 groups, which were significantly lower than that of challenged fish of the S-20 group. All challenged fish of the S-20 group survived. Survival rates over 144 h were 30.0%, 70.0%, and 56.7% for the C-28, C-20, and S-28 groups, respectively. Our results indicated that dietary sodium alginate administration downregulated stress response indicators, enhanced immune responses, and prevented impacts of physiologic stress responses, immunosuppression, and susceptibility to P. damselae subsp. piscicida in grouper subjected to cold stress. Grouper cultured at 28 °C were more susceptible to P. damselae subsp. piscicida infection.
•Grouper fed a sodium alginate-containing diet upregulate anti-stress and immune responses.•Impacts of physiologic stress, immunosuppression under cold-shock stress were ameliorated.•The susceptibility against infection at 28 °C can be decreased by sodium alginate feeding.
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