Emergency contraception: potential role of ulipristal acetate

Unintended pregnancy is a global reproductive health problem. Emergency contraception (EC) provides women with a safe means of preventing unwanted pregnancies after having unprotected intercourse. While 1.5 mg of levonorgestrel (LNG) as a single dose or in 2 doses with 12 hours apart is the currently gold standard EC regimen, a single dose of 30 mg ulipristal acetate (UPA) has recently been proposed for EC use up to 120 hours of unprotected intercourse with similar side effect profiles as LNG. The main mechanism of action of both LNG and UPA for EC is delaying or inhibiting ovulation. However, the ‘window of effect’ for LNG EC seems to be rather narrow, beginning after selection of the dominant follicular and ending when luteinizing hormone peak begins to rise, whereas UPA appears to have a direct inhibitory effect on follicular rupture which allows it to be also effective even when administered shortly before ovulation, a time period when use of LNG is no longer effective. These experimental findings are in line with results from a series of clinical trials conducted recently which demonstrate that UPA seems to have higher EC efficacy compared to LNG. This review summarizes some of the data available on UPA used after unprotected intercourse with the purpose to provide evidence that UPA, a new type of second-generation progesterone receptor modulator, represents a new evolutionary step in EC treatment

Spindle oscillations are generated in the dorsal thalamus and modulated by the thalamic reticular nucleus

Spindle waves occur during the early stage of slow wave sleep and are thought to arise in the thalamic reticular nucleus (TRN), causing inhibitory postsynaptic potential spindle-like oscillations in the dorsal thalamus that are propagated to the cortex. We have found that thalamocortical neurons exhibit membrane oscillations that have spindle frequencies, consist of excitatory postsynaptic potentials, and co-occur with electroencephalographic spindles. TRN lesioning prolonged oscillations in the medial geniculate body (MGB) and auditory cortex (AC). Injection of GABA~A~ antagonist into the MGB decreased oscillation frequency, while injection of GABA~B~ antagonist increased spindle oscillations in the MGB and cortex. Thus, spindles originate in the dorsal thalamus and TRN inhibitory inputs modulate this process, with fast inhibition facilitating the internal frequency and slow inhibition limiting spindle occurrence

Optimal Order Strategy in Uncertain Demands with Free Shipping Option

Free shipping with conditions has become one of the most effective marketing tools; more and more companies especially e-business companies prefer to offer free shipping to buyers whenever their orders exceed the minimum quantity specified by them. But in practice, the demands of buyers are uncertain, which are affected by weather, season, and many other factors. Firstly, we model the centralization ordering problem of retailers who face stochastic demands when suppliers offer free shipping, in which limited distributional information such as known mean, support, and some deviation measures of the random data is needed only. Then, based on the linear decision rule mainly for stochastic programming, we analyze the optimal order strategies of retailers and discuss the approximate solution. Further, we present the core allocation between all retailers via dual and cooperative game theory. The existence of core shows that each retailer is pleased to cooperate with others in the centralization problem. Finally, a numerical example is implemented to discuss how uncertain data and parameters affect the optimal solution

Studies on Anti-Depressant Activity of Four Flavonoids Isolated from Apocynum venetum Linn (Apocynaceae) Leaf in Mice

Purpose: To investigate the anti-depressant activity of kaempferol, quercetin, kaempferol-3-O-β-Dglucose and quercetin-3-O-β-D-glucose isolated from Apocynum venetum Linn. (Apocynaceae) leaf and their mechanisms of action.Methods: The four flavonoids were isolated from Apocynum venetum leaf by chromatography. Mice were divided into vehicle, fluoxetine, kaempferol, quercetin, kaempferol-3-O-β-D-glucose and quercetin- 3-O-β-D-glucose groups (n = 10). Forced swimming (FST), tail suspension (TST) and locomotor activity (LAT) tests were used to evaluate the effects of the four flavonoids (0.35 mM/kg) on immobility time, monoamine neurotransmitters, viz, norepinephrine (NE), dopamine (DA) and 5-hydroxytryptamine (5- HT), as well as on the metabolite (5-HIAA) in mice brain and central nervous system (CNS) with the aid of video camera, HPLC-ECD and activity-monitoring system.Results: The four flavonoids significantly (p < 0.05) reduced mice immobility time (72.58 - 90.24; 52.58 - 70.24 s), 5-HIAA levels (940.8 - 1244.7; 880.8 - 1164.1 ng/g) and 5-HIAA/5-HT ratio (1.77 - 4.76; 1.83 - 4.16), but increased NE, DA and 5-HT levels (238.7 - 405.7, 308.4 - 528.1, 261.4 - 531.9; 243.9 - 423.6, 296.7 - 534.9, 279.8 - 481.4 ng/g) in FST and TST, compared with control group (146.18, 126.18 s; 1363.4, 1240.9 ng/g; 7.43, 6.16; 138.4, 235.4, 183.4 and 143.7, 218.6, 201.4 ng/g). The effects of the four flavonoids on the above indices were significant (p < 0.05) and positively related to their polarity. They had no CNS-stimulating effects in LAT.Conclusion: The anti-depressant activities of the four flavonoids are positively related to their polarity, and the mechanisms may be due to increased NE, DA and 5-HT and reduced 5-HT metabolism.Keywords: Kaempferol, Quercetin, Forced swimming test, Tail suspension test, Locomotor activity test, Neurotransmitter

Plasma indoleamine 2,3-dioxygenase activity as a potential biomarker for early diagnosis of multidrug-resistant tuberculosis in tuberculosis patients

Purpose: Multidrug-resistant tuberculosis (MDR-TB) remains a challenge of global TB control, with difficulty in early detection of drug-sensitive tuberculosis (DS-TB). We investigate the diagnostic significance of IDO as a potential biomarker to discriminate MDR patients among the TB patients. Patients and methods: Plasma indoleamine 2,3-dioxygenase (IDO) was measured by the ratio of kynurenine (Kyn) to tryptophan (Trp) concentrations, using high performance liquid chromatography-mass spectrometry (LC-MS/MS). Chest computed tomography (CT) imaging signs from TB patients were collected and analyzed in 18 DS-TB patients, 16 MDR-TB patients, 6 lung cancer (LC) patients, and 11 healthy individuals. Lung imaging signs from TB patients were collected and analyzed. Results: We found that plasma IDO activity was significantly higher in the MDR-TB patients than in the DS-TB patients (p=0.012) and in the LC patients (p=0.003). We evaluated the diagnostic significance of plasma IDO activity in discriminating the MDR-TB group from the DS-TB group using a receiver operating characteristic (ROC) curve. With a cutoff level of 46.58 uM/mM, the diagnostic sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for IDO activity were 87.50%, 72.22%, 73.68%, and 86.67%, respectively. Plasma IDO activity was higher in cavity cases than in non-cavity cases (p=0.042), proving a positive correlation between lung cavity number and cavity size (p \u3c 0.05, separately) among all the TB patients studied. Conclusion: Our findings confirmed that plasma IDO activity might have an auxiliary diagnosis value for early discrimination of MDR-TB patients from DS-TB patients. Among the TB patients with cavitary lung lesions, higher plasma IDO activity can indicate a higher risk of MDR-TB

Dichloroacetate blocks aerobic glycolytic adaptation to attenuated measles virus and promotes viral replication leading to enhanced oncolysis in glioblastoma

Targeting reprogrammed energy metabolism such as aerobic glycolysis is a potential strategy for cancer treatment. However, tumors exhibiting low-rate glycolysis or metabolic heterogeneity might be resistant to such treatment. We hypothesized that a therapeutic modality that drove cancer cells to high-rate glycolysis might sensitize cancer cells to interference directed against metabolic flux. In this study, we found that attenuated oncolytic measles virus Edmonston strain (MV-Edm) caused glioblastoma cells to shift to high-rate aerobic glycolysis; this adaptation was blocked by dichloroacetate (DCA), an inhibitor of glycolysis, leading to profound cell death of cancer cells but not of normal cells. DCA enhanced viral replication by mitigating mitochondrial antiviral signaling protein (MAVS)-mediated innate immune responses. In a subcutaneous glioblastoma (GBM) xenograft mouse model, low-dose MV-Edm and DCA significantly inhibited tumor growth in vivo. We found that DCA impaired glycolysis (blocking bioenergetic generation) and enhanced viral replication (increasing bioenergetic consumption), which, in combination, accelerated bioenergetic exhaustion leading to necrotic cell death. Taken together, oncolytic MV-Edm sensitized cancer cells to DCA, and in parallel, DCA promoted viral replication, thus, improving oncolysis. This novel therapeutic approach should be readily incorporated into clinical trials

p53/p21 Pathway Involved in Mediating Cellular Senescence of Bone Marrow-Derived Mesenchymal Stem Cells from Systemic Lupus Erythematosus Patients

Our and other groups have found that bone marrow-derived mesenchymal stem cells (BM-MSCs) from systemic lupus erythematosus (SLE) patients exhibited senescent behavior and are involved in the pathogenesis of SLE. Numerous studies have shown that activation of the p53/p21 pathway inhibits the proliferation of BM-MSCs. The aim of this study was to determine whether p53/p21 pathway is involved in regulating the aging of BM-MSCs from SLE patients and the underlying mechanisms. We further confirmed that BM-MSCs from SLE patients showed characteristics of senescence. The expressions of p53 and p21 were significantly increased, whereas levels of Cyclin E, cyclin-dependent kinase-2, and phosphorylation of retinoblastoma protein were decreased in the BM-MSCs from SLE patients and knockdown of p21 expression reversed the senescent features of BM-MSCs from SLE patients. Our results demonstrated that p53/p21 pathway played an important role in the senescence process of BM-MSCs from SLE