Asymptotics for ultimate ruin probability in a by-claim risk model

This paper considers a by-claim risk model with constant interest rate in which the main claim and by-claim random vectors form a sequence of independent and identically distributed random pairs with each pair obeying some certain dependence or arbitrary dependence structure. Under the assumption of heavy-tailed claims, we derive some asymptotic formulas for ultimate ruin probability. Some simulation studies are also performed to check the accuracy of the obtained theoretical results via the crude Monte Carlo method

The Future of Generic Biologics: Should the United States “Follow-On” the European Pathway?

The United States is embarking on a biotechnology drug revolution. In the last few decades, biotech drugs have saved millions of lives, and the market for these miracle cures continues to grow at an astronomical rate. Unfortunately, as the market for biotech drugs is skyrocketing, drug prices are following suit. As Congress strives to make these new drugs more affordable, it must not ignore significant safety concerns unique to these revolutionary therapies. Congress should follow the lead of the European Union to create an accessible pathway for generic forms of biotech drugs that includes strict regulatory measures to ensure drug safety and efficacy

Galactosylated poly(ethylene glycol)-b-poly (l-lactide-co-β-malic acid) block copolymer micelles for targeted drug delivery: preparation and in vitro characterization

Biodegradable galactosylated methoxy poly(ethylene glycol)/poly(l-lactide-co-β-malic acid) (Gal-PEG-b-PLMA) block copolymer micelles were successfully prepared by a solvent diffusion method, and could efficiently encapsulate doxorubicin. The Gal-PEG-b-PLMA micelles before and after doxorubicin loading were characterized by size, morphology, in vitro drug release, and in vitro cytotoxicity in HepG2 cells. Transmission electron microscopy and dynamic light scattering results showed that the empty and doxorubicin-loaded micelles were approximately spherical in shape and had mean sizes of about 72 nm and 85 nm, respectively. In vitro release behavior of doxorubicin from the micelles was pH-dependent, with obviously faster release rates at mildly acidic pH 4.5 and 5.5 compared with physiologic pH 7.4. Methylthiazoletetrazolium assay and flow cytometric analysis indicated that the doxorubicin-loaded galactosylated micelles exhibited a greater growth-inhibitory effect on HepG2 cells than the nongalactosylated doxorubicin-loaded micelles, and induced S phase cell cycle arrest. Confocal laser scanning microscope observations revealed that the galactosylated micelles could be efficiently internalized by HepG2 cells through receptor-mediated endocytosis. The results suggest that Gal-PEG-b-PLMA copolymer micelles are a promising carrier system for targeted drug delivery in cancer therapy

Protective effect of Alhagi sparsifolia against acetaminophen-induced liver injury in mice

Purpose: To investigate the hepatoprotective effects of Alhagi sparsifolia extract against acetaminophen (APAP)-induced liver injury in mice.Methods: Three doses of Alhagi sparsifolia (600, 300 and 150 mg/kg) were were administered to separate groups of mice orally once a day for three days. One-hour after the last dose, APAP (300 mg/kg) was intraperitoneally injected. Liver tissue was taken and tested for levels of serum aspartate aminotransferase (AST) and alanine transaminase (ALT) as biomarkers of liver injury; malonaldehyde (MDA); hydrogen peroxide (H2O2); glutathione (GSH) as an indicator of liver redox; and antioxidant enzyme activity using super oxide dismutase (SOD) assay. Additionally, western blotting was used to measure the expression of protein cytochrome P450 2E1 (CYP2E1) as the key enzyme of APAP metabolism.Results: Blood serum of ALT and AST and levels of CYP2E1 were markedly reduced, while the levels of MDA, H2O2, and SOD were elevated in a dose-dependent manner in mice treated with Alhagi sparsifolia compared to control group treated with APAP alone.Conclusion: The results demonstrate that Alhagi sparsifolia protects mice liver tissue against APAPinduced hepatic injury partly via decreased oxidative stress and inhibition of CYP2E1 expression.Keywords: Alhagi sparsifolia, Polysaccharide, Acetaminophen, CYP2E1, Antioxidan

Hepatoprotective effect of Alhagi sparsifolia against Alcoholic Liver injury in mice

Overconsumption of alcohol leads to alcoholic liver disease (ALD). Natural compounds have been investigated previously for their hepatoprotective activities against liver injury. This study investigated the protective effect of Alhagi sparsifolia on ALD. Alcohol was administered to mice for three consecutive days; either alone or in combination with Alhagi sparsifolia extract (150, 300, 600 mg/kg). Serum aspartate aminotransferase and alanine transaminase as biomarkers of liver injury, the content of malonaldehyde, hydrogen peroxide (H2O2) and glutathione which indicated the redox status of liver and the antioxidant enzyme activity of super oxide dismutase were detected, respectively. Moreover, the expression of protein cytochrome P450 2E1 (CYP2E1) the key enzyme of alcohol metabolism, and also tested by western blot experiment. Subsequently, the mRNA levels of inflammatory factors including TNF- α and TLR4 was determined real-time PCR. Results showed that Alhagi sparsifolia significantly alleviated alcohol-induced liver injury by reducing serum ALT and AST, inhibiting MDA and H2O2 content, increasing SOD, and GSH level in the liver (P< 0.05). In addition, the Alhagi sparsifolia treatment inhibited the expression of CYP2E1 (P< 0.05). The results suggest that Alhagi sparsifolia could be a promising natural substance for ameliorating acute alcohol-induced oxidative stress and hepatic injury

The effects on thermal lesion shape and size from bubble clouds produced by acoustic droplet vaporization

Abstract Background Bubbles formed by acoustic droplet vaporization (ADV) have proven to be an effective method for significant enlargement of the thermal lesions produced by high intensity focused ultrasound (HIFU). We investigated the influences of bubble cloud shape and droplet concentration on HIFU thermal lesions, as these relate to the ADV technique. Methods Unlike previous studies where the droplets were simultaneously vaporized with the HIFU exposure for thermal lesion formation, droplets were vaporized by pulse wave (PW) ultrasound prior to continuous wave (CW) ultrasound heating in this experimental study. Under different experimental conditions, we recorded and quantified by the image processing methods the morphology and size of the bubble clouds created and the corresponding thermal lesions formed. Results The results demonstrated that different ADV droplet concentrations produced a variety of thermal lesion shapes and sizes. The lesion volume could be increased using PW ultrasound followed by CW exposure, especially for higher droplet concentrations, e.g. 3.41 × 106/mL yielded a tenfold increase over that seen using CW alone. Conclusion These findings could lead to optimization of HIFU therapy by selecting a bubble forming strategy and droplet concentrations, especially using lower ultrasound powers which is desirable in clinical applications.https://deepblue.lib.umich.edu/bitstream/2027.42/146148/1/12938_2018_Article_596.pd

Bryostatin 1 alleviates respiratory syncytial virus pneumonia in a mice model via down-regulation of inflammatory cytokines

Purpose: To investigate the effect of bryostatin 1 on respiratory syncytial virus (RSV) infection in vitro in lung alveolar cells and in vivo in a mice model. Methods: RSV infection in the mice was induced by the administration of 2 x 106 PFU viral particles intranasally in the left nostril. Reverse transcription-polymerase chain reaction (RT-PCR) and western blotting were used for the determination of changes in interleukin expression. Results: Bryostatin 1 treatment of RSV-infected BEAS-2B cells significantly (p < 0.05) inhibited viability. The mortality of mice infected with RSV markedly decreased on treatment with bryostatin 1. The pulmonary damage induced by RSV infection was also prevented in mice treated with bryostatin 1. Treatment of the RSV infected mice with bryostatin 1 caused a dose-based suppression of IL 1β/ 18 and TNF α generation (p < 0.05). Bryostatin 1 pre-treatment at doses 2, 6 and 12 mg/kg led to reduction of NLRP3, ASC and caspase 1 proteins, as well as a significant decrease in the expression of mRNA corresponding to NLRP3, ASC and caspase 1 (p< 0.05). Conclusion: The results demonstrate that bryostatin 1 treatment of RSV-infected BEAS-2B cells prevents reduction in its viability. Moreover, pre-treatment of RSV-infected mice with bryostatin 1 improves mortality and prevents pulmonary tissue damage by down-regulating NLRP3 activation. Therefore, bryostatin 1 may be an option for the development of an effective treatment for pneumoni

Dietary Supplementation With High Fiber Alleviates Oxidative Stress and Inflammatory Responses Caused by Severe Sepsis in Mice Without Altering Microbiome Diversity

In this study, we demonstrated the effects of a high-fiber diet on intestinal lesions, oxidative stress and systemic inflammation in a murine model of endotoxemia. C57BL/6 mice were randomly assigned to four groups: the control group (CONTROL), which received a commercial normal-fiber rodent diet comprising normal fiber; a CLP group, which received a commercial normal-fiber rodent diet and underwent caecal ligation puncture (CLP); a high-fiber group (HFG), which received a commercial high-fiber rodent diet; and a high fiber + CLP group (HFCLP) which received a commercial high-fiber rodent diet and underwent CLP (30%). The sepsis model was created via CLP after 2 weeks of dietary intervention. Notably, dietary high-fiber supplementation in HFCLP group improved survival rates and reduced bacterial loads, compared with CLP alone. In the HFCLP group, dietary fiber supplementation decreased the serum concentrations of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6) and high-mobility group protein 1 (HMG-1) but raised the concentration of interleukin 10 (IL-10), compared with the levels in CLP mice. Meanwhile, high-fiber supplementation increased the relative proportions of Akkermansia and Lachnospiraceae. These data show that dietary high-fiber supplementation may be therapeutic for sepsis-induced lesions

A long‐term obesogenic high‐fat diet in mice partially dampens the anti‐frailty benefts of late‐life intermittent fasting

The global obesity pandemic coupled with ever-growing life expectancies equates to hundreds of millions of individuals with potentially longer but not healthier lives. Aging is one of the risk factors for numerous maladies such as metabolic dis- order and frailty, which are exacerbated under obesity. Thus, therapeutic approaches that address obesity to ultimately improve afected individuals’ quality of life and extend their lifespan are needed. We previously reported that the every other day (EOD) fasting initiated late-life improved metabolic, musculoskeletal, and cognitive endpoints in standard rodent diet-fed mice. In the present study, using the same dietary intervention methodology, we tested if 2.5 months of EOD fasting could improve metabolic, physiological, and cognitive endpoints in mice after an 18 month obesogenic high-fat diet (HFD). The positive efects of EOD fasting were generally consistent across the endpoints; EOD fasting decreased total body mass, maintained more %lean mass, improved glucose tol- erance and utilization, and improved neuromuscu- lar function. In contrast to our previous study, grip strength, hippocampal-dependent memory, and renal hydrogen sulfde (H2S) production were not improved by the HFD EOD fasting. Thus, efcacy for late- life initiated intermittent fasting to improve specifc frailty markers may be partially dependent on nutritional compositions of the diet