Different effects of meteorological factors on hand, foot and mouth disease in various climates: a spatial panel data model analysis.

BACKGROUND: Major outbreaks of hand, foot and mouth disease (HFMD) have been reported in China since 2008, posing a great threat to the health of children. Although many studies have examined the effect of meteorological variables on the incidence of HFMD, the results have been inconsistent. This study aimed to quantify the relationship between meteorological factors and HFMD occurrence in different climates of mainland China using spatial panel data models. METHODS: All statistical analyses were carried out according to different climate types. We firstly conducted a descriptive analysis to summarize the epidemic characteristics of HFMD from May 2008 to November 2012 and then detected the spatial autocorrelation of HFMD using a global autocorrelation statistic (Moran's I) in each month. Finally, the association between HFMD incidence and meteorological factors was explored by spatial panel data models. RESULTS: The 353 regions were divided into 4 groups according to climate (G1: subtropical monsoon climate; G2: temperate monsoon climate; G3: temperate continental climate; G4: plateau mountain climate). The Moran's I values were significant with high correlations in most months of group G1 and G2 and some months of group G3 and G4. This suggested the existence of a high spatial autocorrelation with HFMD. Spatial panel data models were more appropriate to describe the data than fixed effect models. The results showed that HFMD incidences were significantly associated with average atmospheric pressure (AAP), average temperature (AT), average vapor pressure (AVP), average relative humidity (ARH), monthly precipitation (MP), average wind speed (AWS), monthly total sunshine hours (MSH), mean temperature difference (MTD), rain day (RD) and average temperature distance (ATD), but the effect of meteorological factors might differ in various climate types. CONCLUSIONS: Spatial panel data models are useful and effective when longitudinal data are available and spatial autocorrelation exists. Our findings showed that meteorological factors were related to the occurrence of HFMD, which were also affected by climate type.

[Cigarette smoking in different manners induces acute lung injury in rats].

Objective: To investigate the effects of cigarette smoking in different manners on acute lung injury in rats. Methods: The commercially available cigarettes with tar of 1,5, 11 mg were smoked in Canada depth smoking (health canada method, HCM) manner, and those with tar of 11 mg were also smoked in international standard (ISO) smoking manner. Rats were fixed and exposed to mainstream in a manner of nose-mouth exposure. After 28 days, the bronchoalveolar lavage fluids from left lung were collected for counting and classification of inflammatory cells and determination of pro-inflammatory cytokines IL-1ß and TNF-α. The right lungs were subjected to histological examination and determination of myeloperoxidase (MPO) and superoxide dismutase (SOD) activities and glutathione, reactive oxygen species (ROS) and malondialdehyde (MDA) levels. Results: In both HCM and ISO manners, the degree of lung injury was closely related to the tar content of cigarettes, and significant decrease in the body weight of rats was observed after smoking for one week. In a HCM manner, smoking with cigarette of 11 mg tar resulted in robust infiltration of macrophages, lymphocytes and neutrophils into lungs, significant increase in IL-1ß and TNF-α levels and MPO activities, and significant decrease in GSH levels and SOD activities and increase in ROS and MDA levels (all P<0.05). Smoking with cigarette of 5 mg tar led to moderate increase in IL-1ß and TNF-α levels, and MPO activities (all P<0.05), and moderate decrease in GSH levels and SOD activities and increase of ROS and MDA levels (all P<0.05). However, smoking with cigarette of 1 mg tar affected neither inflammatory cell infiltration nor IL-1ß and TNF-α levels. Conclusion: Cigarette smoking in nose-mouth exposure manner can induce acute lung injury in rats; and the degree of lung injury is closely related to the content of tar and other hazards in cigarettes.

Design and evaluation of oseltamivir phosphate dual-phase extended-release tablets for the treatment of influenza.

In this study, once-daily extended-release tablets with dual-phase release of oseltamivir phosphate were developed for the treatment of influenza. The goal was to improve patient adherence and offer more therapeutic choices. The tablets were manufactured using wet granulation, bilayer tablet compression, and enteric membrane-controlled coating processes. Various polymers, such as hydroxypropyl methylcellulose (HPMC K100MCR, K15MCR, K4MCR, K100LV), enteric polymers (HPMC AS-LF, Eudragit L100-55) and membrane-controlled polymers (OPADRY® CA), were used either individually or in combination with other common excipients. The formulations include enteric-coated extended-release tablet (F1), hydrophilic matrix extended-release tablet (F2), semipermeable membrane-controlled release tablet (F3) and a combination extended-release tablet containing both enteric and hydrophilic matrix (F4). The in vitro drug release profile of each formulation was fitted to the first-order model, and the Ritger-Peppas model suggested that Fickian diffusion was the primary mechanism for drug release. Comparative bioequivalence studies with Tamiflu® (oseltamivir phosphate) capsules revealed that formulations F1, F2, and F3 did not achieve bioequivalence. However, under fed conditions, formulation F4 achieved bioequivalence with a relative bioavailability of 95.30% (90% CI, 88.83%-102.15%). This suggests that the formulation F4 tablet could potentially be a new treatment option for patients with influenza.

N-Nitrosodimethylamine formation in metformin hydrochloride sustained-release tablets: Effects of metformin and hypromellose used in drug product formulation.

In recent years, nitrosamines have been discovered in some types of drug products that becomes a current regulatory hotspot, and have attracted a lot attention from both regulatory authorities and industry. This manuscript provided an industry perspective on the nitrosamines research. A liquid chromatography coupled with tandem mass spectrometry（LC-MS/MS）method was developed and applied for the quantification of N-nitrosodimethylamine (NDMA) in metformin hydrochloride sustained-release tablets (MET). The key factors resulting in the NDMA formation in MET were identified through forced degradation and drug-excipient studies, which included high temperature, dimethylamine, strong alkali and oxidation conditions, peroxide and alkaline components contained in the formulation as well as the nitrite and nitrate impurities that might be presented in certain excipients. Further, API particle size and water content of the drug product would also affect the growth rate of NDMA. Therefore, the following mitigation strategies to reduce the risk of nitrosamines in the finished drug product are proposed in this manuscript: 1) avoid the use of excipients containing nitrite, nitrate and peroxide impurities; 2) avoid high temperature and strong alkaline environment in the production and storage condition; 3) maintain an appropriate water content level in the formulation. Based on the above principles, it was recommended to add antioxidant or incorporate excipient such as Na2CO3 to modify the formulation pH to weak basic environment in the formulation of MET, which can could effectively prevent formation of NDMA in the stability process.

The RNA Methyltransferase METTL3 Promotes Endothelial Progenitor Cell Angiogenesis in Mandibular Distraction Osteogenesis via the PI3K/AKT Pathway.

Distraction osteogenesis (DO) is used to treat large bone defects in the field of oral and maxillofacial surgery. Successful DO-mediated bone regeneration is dependent upon angiogenesis, and endothelial progenitor cells (EPCs) are key mediators of angiogenic processes. The N6-methyladenosine (m6A) methyltransferase has been identified as an important regulator of diverse biological processes, but its role in EPC-mediated angiogenesis during DO remains to be clarified. In the present study, we found that the level of m6A modification was significantly elevated during the process of DO and that it was also increased in the context of EPC angiogenesis under hypoxic conditions, which was characterized by increased METTL3 levels. After knocking down METTL3 in EPCs, m6A RNA methylation, proliferation, tube formation, migration, and chicken embryo chorioallantoic membrane (CAM) angiogenic activity were inhibited, whereas the opposite was observed upon the overexpression of METTL3. Mechanistically, METTL3 silencing reduced the levels of VEGF and PI3Kp110 as well as the phosphorylation of AKT, whereas METTL3 overexpression reduced these levels. SC79-mediated AKT phosphorylation was also able to restore the angiogenic capabilities of METTL3-deficient EPCs in vitro and ex vivo. In vivo, METTL3-overexpressing EPCs were additionally transplanted into the DO callus, significantly enhancing bone regeneration as evidenced by improved radiological and histological manifestations in a canine mandibular DO model after consolidation over a 4-week period. Overall, these results indicate that METTL3 accelerates bone regeneration during DO by enhancing EPC angiogenesis via the PI3K/AKT pathway.

Hypoxia improved vasculogenesis in distraction osteogenesis through Mesenchymal-Epithelial transition (MET), Wnt/ß-catenin signaling pathway, and autophagy.

INTRODUCTION: The osteogenesis rate of distraction osteogenesis is 4-6 times faster than that of infants, far beyond fracture healing. However, the osteogenesis mechanism of DO is complicated and inconclusive owing to two significant elements: mechanical tension which is well explored and trauma caused by bone fracture. Vasculogenesis and EPCs are critical for successful bone regeneration during DO. Thus, this study aimed to explore the effects of hypoxia caused by trauma or CoCl2 on the vasculogenesis of DO and EPCs. MATERIAL AND METHODS: Mandibular DO and BF models were generated using 6 beagle dogs with a distraction rate of 1 mm per day for 7 days or acute lengthening for 7 mm. The vasculogenesis in DO-gap or BF-gap were assessed via histological analyses, qRT-PCR and immunofluorescence staining. Dog bone marrow EPCs were isolated and cultured with or without 0.1 mM CoCl2. The effect of hypoxia caused by CoCl2 were subsequently valuated via in vitro assays including Cell Counting Kit-8, transwell assay, qRT-PCR, western blot, and immunofluorescence staining. RESULTS: Histological analyses, qRT-PCR and immunofluorescence staining revealed that vasculogenesis markedly accelerated in DO-gap compared with BF-gap, and the DO-gap displayed more positive to CD133, CD34, HIF-1α, E-cadherin, beclin1, ß-catenin, VEGF, bFGF, and less positive to ZEB1 than BF-gap. In addition, in vitro analyses revealed CoCl2 treatment enhanced EPCs proliferation and migration, and the levels of HIF-1α, E-cadherin, ß-catenin, beclin1, VEGF, bFGF of EPCs were increased, but the level of ZEB1 was decreased. CONCLUSION: Our studies showed that hypoxia promoted vasculogenesis in DO and EPCs, and the mechanism may involve autophagy, Wnt/ß-catenin signaling pathway, and Mesenchymal-Epithelial transition (MET).

Fabrication of cross-linked chitosan beads grafted by polyethylenimine for efficient adsorption of diclofenac sodium from water.

Diclofenac sodium (DS) is an emerging contaminant that is toxic and remains at high concentrations in natural aquatic environments. The aim of this study was to fabricate a novel spherical polymeric adsorbent composed of cross-linked chitosan beads grafted by polyethylenimine (PEI) to remove DS from water. The adsorbents were thoroughly characterized using Fourier transform infrared spectroscopy, scanning electron microscopy, elemental analyses, and X-ray photoelectron spectroscopy. A cross-linking step was expected to enhance adsorption. The experimental data obtained from a series of adsorption experiments were fit well by the Langmuir isotherm model and pseudo-second-order model. The epichlorohydrin-PEI adsorbent (EPCS@PEI) showed a maximum adsorption capacity of 253.32 mg/g and removal efficiency of nearly 100% for the DS in the initial 50 mg/L solution. Therefore, EPCS@PEI is proposed as a potential adsorbent for DS removal, where these initial findings are expected to promote further design and fabrication of effective adsorbents for practical applications.

Stabilization of zein nanoparticles with k-carrageenan and tween 80 for encapsulation of curcumin.

We aimed to develop a stable nanosystem with k-carrageenan (Kc), an anionic polysaccharide, combined with tween 80 to stabilize zein nanoparticles. The experimental results showed that the particle size, zeta-potential, and stability of the system depend on the Kc amount when the zein amount was unchanged. We found that the nanosystem with 5.0 and 10.0 mg Kc had a smaller particle size (250.1 ± 0.9 and 287.6 ± 1.4 nm, respectively), low polydispersity index (PDI, ≤ 0.20), and high stability when the external conditions changed. No obvious flocculation or deposition was observed at pH of 3-9, salt ion concentrations of 0-500 mmol/L, temperature of 30 °C and 50 °C-90 °C, and storage at 4 °C for 30 days. When the Kc-ZNP system was loaded with curcumin (Cur), there was a good encapsulation effect (5.0 mg Kc with 1.00 mg Cur (EE (%) = 34.69% ± 2.02%, size = 380.23 ± 5.80 nm, PDI = 0.252 ± 0.018) and 10.0 mg Kc with 2.00 mg Cur (EE (%) = 20.13% ± 1.05%, size = 431.27 ± 0.78 nm, PDI = 0.269 ± 0.020), ensuring that the particle size was not too large. Therefore, Kc-ZNPs could be a potential delivery system for fat-soluble drugs.

Spatiotemporal Cluster Patterns of Hand, Foot, and Mouth Disease at the County Level in Mainland China, 2008-2012.

BACKGROUND: Hand, foot, and mouth disease (HFMD) is known to be a highly contagious childhood illness. In recent years, the number of reported cases of HFMD has significantly increased in mainland China. This study aims at the epidemiological features, spatiotemporal patterns of HMFD at the county/district level in mainland China. METHODS: Data on reported HFMD cases for each county from 1 January 2008 to 31 December 2012 were obtained from the Chinese Center for Disease Control and Prevention. Cluster analysis, spatial autocorrelation, and retrospective scan methods were used to explore the spatiotemporal patterns of the disease. RESULTS: The annual incidences varied greatly among the counties, ranging from 0 to 74.31‰ with the median of 5.42‰ (interquartile range: 1.54‰-13.55‰) during 2008-2012 in mainland China. Counties close to provincial capital cities generally had higher incidences than rural counties. A seasonal distribution was observed between the northern and southern China, of which dual epidemic were shown in southern China and usually only one in northern China. Based on the global and local spatial autocorrelation analysis, we found that the spatial distribution of HFMD was presented a significant clustering pattern for each year (P<0.001), and hotspots of the disease were mostly distributed in coastal provinces of China. The retrospective scan statistic further identified the dynamics of spatiotemporal clustering areas of the disease, which were mainly distributed in the counties of eastern and southern China, as well as provincial capitals and their surrounding counties. CONCLUSIONS: The spatiotemporal clustering areas of the disease identified in this way were relatively stable, and imminent public health planning and resource allocation should be focused within those areas.

Vaccination strategies to enhance local immunity and protection against Mycobacteriun tuberculosis.

To determine the immunogenicity and protective efficacy of the Mycobacterium tuberculosis 10 kD culture filtrate protein (CFP10), and to evaluate strategies that enhance local immunity, we used C57Bl/6 DR4 mice that were transgenic for human HLA DRB1 0401, because CFP10 contains epitopes for DRB1 0401 but not for C57Bl/6 mice. Intramuscular immunization with a DNA vaccine encoding CFP10 elicited production of IFN-gamma by systemic CD4+ T cells, and one intravenous dose of the CFP10-based DNA vaccine coated with polyethylenimine (PEI) stimulated IFN-gamma production by lung CD4+ cells and reduced the pulmonary bacillary burden. We conclude that CFP10 is a potential vaccine candidate and that coating vaccines with PEI enhances local protective immunity to tuberculosis