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Osteoporotic fracture introduce enormous societal and economic burden, especially for long-term care residents (LTCRs). Although osteoporosis prevention for LTCRs is urgently needed, obstacles such as frail status and inconvenient hospital visits hurdled them from necessary examinations and diagnoses. We aimed to test 10 existing osteoporosis screening tools (OSTs), which can be easily used in institutions and serve as a prediction, for accurately determining the outcome of a Taiwan's National Health Insurance (NHI)-reimbursed anti-osteoporosis medications (AOMs) application for LTCRs.This prospective analysis recruited 444 patients from LTC institutions between October 2018 and November 2019. Predictions of whether the NHI-reimbursed AOMs criteria was met were tested for 10 OSTs. The results of OSTs categorized into self-reported or validated based on previous fracture history were self-reported by LTCRs or validated by imaging data and medical records, respectively. The receiver operating characteristic curve and the optimal cut-off points for LTCRs based on Youden's index were explored.Overall, the validated OSTs had a higher positive predictive value (PPV) and negative predictive value (NPV) summation than the corresponding reported OSTs. The validated FRAX-Major was the best OST (PPV = 63.6%, NPV = 82.4% for the male group and, PPV = 78.8%, NPV = 90.0% for the female group). After applying the optimum cut-off derived from Youden's index, the validated FRAX-Major (PPV = 75.4%, NPV = 92.0%)) remained performed best for men. In female population, validated FRAX-Major (PPV = 87.2%, NPV = 84.1%) and validated osteoporosis prescreening risk assessment (OPERA; PPV = 96.1%, NPV = 79.7%)) both provided good prediction results.FRAX-Major and OPERA have better prediction ability for LTCRs to acquire NHI-reimbursed AOMs. The validated fracture history and adjusted cut-off points could prominently increase the PPV during prediction.

Oligonucleotide aptamers are an important kind chemical antibody-like functional biomolecules. The aptamer-based mass spectrometric techniques can not only provide molecular mass and characteristic structures by mass spectrometry, but show high sensitivity and high affinity enrichment towards target molecules by aptamers. This review summarizes the advances in the aptamer- based mass spectrometric applications, and highlights the progress of aptamer-target interaction characterization, as well as the applications of aptamer as off-line or on-line affinity materials in mass spectrometric techniques. It suggests that the combination of various new mass spectrometric techniques, the construction or combination of varied pretreatment or on-line signal amplification approaches, especially the applications of aptameric functional nanomaterials, should be focused in the aspects of interaction characterization, selective extraction and highly sensitive detection of trace target molecules. The prospects of the development were also described.

The endothelium is the critical barrier that controls transendothelial communications. Blood vessels in cancer tissue are poorly developed and highly permeable. However, it is poorly understood how circulating cancer cells released through these "leaky" vessels break the intact vasculature of remote organs to metastasize. We investigated the roles of cancer cell-derived extracellular vesicles (CEVs) in regulating cancer metastasis by analyzing samples from gastric cancer patients, performing in vitro experiments, and studying mouse models. We made several novel observations. First, the rate of metastasis was closely associated with plasma levels of CEVs in patients with gastric cancer. Second, cultured endothelial cells endocytosed CEVs, resulting in cytoskeletal rearrangement, low expression of the junction proteins cadherin and CD31, and forming large intercellular gaps to allow the transendothelial migration of cancer cells. The dynamin inhibitor Dynasore prevented these CEV-induced changes of endothelial cells by blocking CEVs endocytosis. Third, CEVs disrupted the endothelial barrier of cancer-bearing mice to promote cancer metastasis. Finally, lactadherin promoted the clearance of circulating CEVs to reduce metastasis. These results demonstrate the essential role of CEVs in promoting the metastasis of gastric cancer.

The global incidence and prevalence of inflammatory bowel disease (IBD) has increased over the last 2-4 decades, likely because of the adoption of a more “western” lifestyle as well as improved detection and awareness, and Taiwan is no exception. To characterize the increasing burden of IBD, we conducted a comprehensive review of IBD in the existing literature. The following parameters were reviewed: background knowledge and current standard care for IBD, including natural history, epidemiology, pathogenesis, diagnosis, monitoring, and treatment. In addition, new imaging modalities and treatment options such as combined positron emission tomography and magnetic resonance enterography, new biologic agents, small-molecule therapy, biosimilar therapeutics, mesenchymal stem cell transplantation, and fecal microbiota transplantation, all of which have been introduced for IBD management, were reviewed. We also used the hospital-based as well as population-based Taiwan National Health Insurance Research Database to assess Taiwan-specific trends for comparison with global trends. Keywords: Inflammatory bowel disease, 2018, Update

Objective This study investigated the effect of delayed or missed doses on the pharmacokinetics (PK) of lamotrigine (LTG) in children with epilepsy and established remedial dosing recommendations for nonadherent patients. Methods The Monte Carlo simulation based on a published LTG population PK model was used to assess the effect of different scenarios of nonadherence and the subsequently administered remedial regimens. The following three remedial approaches were investigated for each delayed dose: A) A partial dose was administered immediately, and the regular dose was administered at the next scheduled time. B) The delayed dose was administered immediately, followed by a partial dose at the next scheduled time. C) The delayed and partial doses were coadministered immediately, the next scheduled dose was skipped, and the regular dosing was resumed at the subsequent scheduled time. The most appropriate remedial regimen was that with the shortest deviation time from the individual therapeutic window. Results The effect of nonadherence on PK was dependent on the delay duration and daily dose, and the recommended remedial dose was related to the delay duration and concomitant antiepileptic drugs. Remedial dosing strategies A and B were almost equivalent, whereas C showed a larger PK deviation time. If one dose was missed, double doses were not recommended for the next scheduled time. Conclusions Simulations provide quantitative insight into the remedial regimens for nonadherent patients, and clinicians should select the optimal regimen based on the status of patients.

As a novel micro-reactor, the microporous tube-in-tube microchannel reactor (MTMCR) has been applied to some processes such as gas absorption, preparation of nanomaterials for the past few years. In this work, the three-dimension simulations in the microporous tube-in-tube microchannel reactor (MTMCR) have been carried out via computational fluid dynamics (CFD) to study the influence of various parameters on gas–liquid flow behaviors, and the coupled level set and volume of fluid method was applied to capture the gas–liquid interface. The liquid distribution in MTMCR by CFD was basically in agreement with the results of visualization experiment and the time-averaged pressure drops were in agreement with literature data within deviation of ±5%. The simulation results showed that the interfacial area and pressure drop increased with the increase of gas or liquid flow rates. The smaller micropores size and annular channel width led to a larger interfacial area and higher pressure drop. Three typical liquid flow patterns were revealed: droplet flow, elongated-droplet flow and churn flow, and the interfacial areas ranged from 976 to 9172 m2/m3 under operating conditions. This work indicated the great potential of the MTMCR for intensifying the gas–liquid mass transfer process, and provided theoretical basis of the MTMCR for practical applications.

We propose a novel method to compute multi-loop master integrals by constructing and numerically solving a system of ordinary differential equations, with almost trivial boundary conditions. Thus it can be systematically applied to problems with arbitrary kinematic configurations. Numerical tests show that our method can not only achieve results with high precision, but also be much faster than the only existing systematic method sector decomposition. As a by product, we find a new strategy to compute scalar one-loop integrals without reducing them to master integrals., Comment: references added, version published in PLB

HO-1 (heme oxygenase-1), an antioxidant enzyme, induced by rosiglitazone (PPAR ligands) can be a potential treatment of inflammation. However, the mechanisms of rosiglitazone-induced HO-1 expression in human pulmonary alveolar epithelial cells (HPAEpiCs) remain largely unknown. In this study, we found that upregulation of HO-1 in vitro or in vivo by rosiglitazone attenuated VCAM-1 gene expression and monocyte adhesion to HPAEpiCs challenged with lipopolysaccharide (LPS). The inhibitory effects of rosiglitazone on LPS-mediated responses were reversed by transfection with HO-1 siRNA. LPS-induced VCAM-1 expression was mediated through NF-κB activation which was attenuated by rosiglitazone via suppressing p65 activation and translocation into the nucleus. Moreover, pretreatment with the inhibitor of PKCs (H7), PKCα (Gö6976), AMPKα (Compound C), p38 MAPKα (p38i VIII), SIRT1 (Sirtinol), or PPARγ (T0070907) and transfection with siRNA of PKCα, AMPKα, p38 MAPKα, SIRT1, or PPARγ abolished the rosiglitazone-induced HO-1 expression in HPAEpiCs. Further studies indicated that rosiglitazone stimulated SIRT1 deacetylase leading to PGC1α translocation from the cytosol into the nucleus, promoting fragmentation of NCoR and phosphorylation of PPARγ. Subsequently, PPARγ was activated by phosphorylation of PKCα, AMPKα, p38 MAPKα, and SIRT1, which turned on transcription of HO-1 gene by binding to PPAR response element (PPRE) and enhancing PPARγ promoter activity. These results suggested that rosiglitazone-induced HO-1 expression is mediated through PKCα/AMPKα/p38 MAPKα/SIRT1-dependent deacetylation of Ac-PGC1α and fragmentation of NCoR/PPARγ activation in HPAEpiCs. Up-regulation of HO-1 protected against the inflammatory responses triggered by LPS, at least in part, through attenuation of NF-κB.

Histone deacetylase (HDAC) is a validated drug target for various diseases. This study combined indole recognition cap with SAHA, an FDA-approved HDAC inhibitor used to treat cutaneous T-cell lymphoma (CTCL). The structure activity relationship of the resulting compounds that inhibited HDAC was disclosed as well. Some compounds exhibited much stronger inhibitory activities than SAHA. We identified two meta-series compounds 6j and 6k with a two-carbon linker had IC50 values of 3.9 and 4.5 nM for HDAC1, respectively. In contrast, the same oriented compounds with longer carbon chain linkers showed weaker inhibition. The result suggests that the linker chain length greatly contributed to enzyme inhibitory potency. In addition, comparison of enzyme-inhibiting activity between the compounds and SAHA showed that compounds 6j and 6k displayed higher inhibiting activity for class I (HDAC1, -2, -3 and -8). The molecular docking and structure analysis revealed structural differences with the inhibitor cap and metal-binding regions between the HDAC isozymes that affect interactions with the inhibitors and play a key role for selectivity. Further biological evaluation showed multiple cellular effects associated with compounds 6j- and 6k-induced HDAC inhibitory activity.

The heavy ion fusion–evaporation reaction study for the high-spin spectroscopy of 75As has been performed via the reaction channel 70Zn(9Be, 1p3n)75As at a beam energy of 42 MeV. The collective structure especially a dipole band in 75As is established for the first time. The properties of this dipole band are investigated in terms of the self-consistent tilted axis cranking covariant density functional theory. Based on the theoretical description and the examination of the angular momentum components, this dipole band can be interpreted as a novel stapler band, where the valence neutrons in ( 1 g 9 / 2 ) orbital rather than the collective core are responsible for the closing of the stapler of angular momentum.

Hepatocellular carcinoma (HCC) is a highly aggressive solid malignancy in the word. Aberrant microRNA (miRNA) expression is involved in human diseases including cancer. In the current study, we explore the function of miR-98 in HCC cell proliferation. We found that expression level of miR-98 was significantly decreased in HCC tissues and cells lines compared with adjacent non-tumor issues and human hepatic cell line LO2. Increased expression of miR-98 suppressed HCC cell proliferation and arrested HCC cell cycle in G0/G1 phase. While, suppressed expression of miR-98 showed the opposite effect. Bioinformatics analysis revealed EZH2, a putative tumor promoter as a potential target of miR-98. Additionally, luciferase reporter assay revealed that miR-98 directly binds to the 3'-untranslated region (3'-UTR) of EZH2 mRNA. Furthermore, we demonstrated that miR-98 could reduce the Wnt/β-catenin signal pathway by suppressing EZH2 directly. Moreover, inhibition of EZH2 abrogated the effect of miR-98 inhibitor on HCC cell proliferation. Taken together, these results suggested that miR-98 functioned as a potential tumor suppressor by regulating Wnt/β-catenin signal pathway through direct suppression of EZH2 expression and might sever as a potential therapeutic target for HCC patients.

Throughout the course of evolution, organisms have produced biominerals with hierarchical structures derived from organic templates. Over the last couple of decades, scientists have adopted sophisticated structures as templates for preparing pure or hybrid inorganic materials that bear the same morphologies as their biological counterparts. The present review provides a broad overview on the state-of-the-art research in the field of mineralized inorganic and hybrid materials, using functional biological or synthetic templates that have been adopted for biomedical, physical, chemical and environmental applications. The synthesis, properties, and progress of these bio-inspired materials are reviewed to provide a backdrop for future research in various arenas.

A laboratory study was conducted to determine the effects of membrane filtration treatment on the performance of recirculating aquaponic system and the production of tilapia ( Oreochromis niloticus ♂ × Oreochromis mossambicus ♀) and water spinach ( Ipomoea aquatica ). The recirculation system consisted of a fish tank, a sludge tank with membrane filtration treatment, and a hydroponic tank. The control had the same experimental arrangement excluding the membrane. The experiment was continued for 12 weeks. Final weight gain and specific growth rate of tilapia, and total yield of plants in the membrane filtration system were 69%, 54%, and 34% higher than that of the control, respectively. Furthermore, the membrane treatment effectively retained the microbes and solids in the sludge tank that consequently increased the nitrification process and also showed higher levels of biological oxygen demand (BOD), bacteria, turbidity, and suspended solids than the control. Therefore, the average NH 4 + - N , NO 2 − - N , BOD, chemical oxygen demand (COD), total bacterial count, and turbidity in the fish tank and the plant tank of the membrane filtration system were significantly lower than that in the control.

Objective Trisomy 18 is one of the major numerical chromosomal disorders. The incidence of trisomy 18 is approximately one in 6000 live births. Dandy–Walker malformation (DWM) is the most common congenital malformation of the cerebellum, with an incidence of about one in 5000 live births. The incidence of trisomy 18 associated with DWM is rare and long-term survival rate is very low. Case report A case involving a 39-year-old pregnant female with a case of trisomy 18 associated with DWM. Conclusion The incidence of trisomy 18 associated with DWM is rare, and our report presents an unusual case that supplements our knowledge of this condition. We report a case involving a 39-year-old pregnant female with a case of trisomy 18 associated with Dandy–Walker malformation (DWM). Fetal ultrasonography showed hypoplasia of the cerebellar vermis and dilatation of the fourth ventricle and was characterized by an enlarged posterior fossa. Fetal magnetic resonance imaging showed inferior vermian hypoplasia and a large posterior fossa cyst communicating with the fourth ventricle causing high insertion of the torcular herophili, which was compatible with DWM. Furthermore, the karyotyping report revealed trisomy 18. The incidence of trisomy 18 associated with DWM is rare, and our report presents an unusual case that supplements our knowledge of this condition.

Two new copper(II) complexes, 9-PMAH-Cu (1) and 9-FPMAH-Cu (2), of anthrahydrazone were synthesized and structurally characterized, in which 9-FPMAH (9-(4'-trifluoromethyl)-pyrimidine anthrahydrazone) is the 4'-CF3 derivative of 9-PMAH (9-pyrimidine anthrahydrazone). Both complexes 1 and 2 showed similar intercalative binding modes towards DNA and might compete with the typical DNA intercalator, GelRed, in the same binding site. They could also act as topoisomerase (type I) suppressor to effectively inhibit its activity, in which complex 1 was more effective than 2. The in vitro antitumor screening indicated that complex 1 displayed much higher antiproliferative ability than 2 and cisplatin towards all the tested tumor cell lines. On the other hand, complex 1 also showed high cytotoxicity against human normal liver cell line HL-7702, suggesting it is a potential high cytotoxic antitumor candidate. While it was also suggested that the loss of activity of complex 2 might be due to the presence of 4'-CF3 on the pyrimidine ring. Studies on the cellular level showed that complex 1 could arrest the cell cycle of the most sensitive T-24 cells at G2/M phase and induced cell apoptosis. Complex 1 further showed a significant suppression on the tumor growth on the T-24 tumor xenograft mouse model, but not reduced the body weight. Especially, complex 1 could retain its coordination state in H2O even in the presence of HSA. The results suggests that complex 1 is of enough safety to be considered as a promising anticancer candidate by combining the bioactive Cu(II) and the anthrahydrazone pharmacophore.

Objective The optimal time after hip fracture to start prophylactic anti-osteoporosis medications (AOMs) remains uncertain, especially in real-world practice. Therefore, we investigated how timing of AOMs initiation affects the risk of subsequent osteoporotic fractures, and what factors influence timing of AOMs prescription. Method Patients ≥50 years old with diagnostic codes indicating hospitalization for hip fracture (n = 77,930) were identified from the Taiwan National Health Insurance Research Database; 9986 who were prescribed AOMs ≤1 year after a newly-diagnosed hip fracture were grouped into those who started AOMs from: ≤14 days (very early); 15–84 days (early); 85–252 days (late); and 253–365 days (very late). Associations with fracture-related hospitalizations after an index fracture were analyzed using a multivariate, time-dependent Cox proportional hazards model, and between-group differences compared by log-rank testing. Factors influencing timing of AOMs initiation were elucidated using multivariate logistic regression analyses. Results Compared to AOMs initiation from 15 to 84 days, initiation after 252 days was associated with significantly increased risk of fracture-related hospitalization (HR = 1.93, 95% CI 1.29–2.89). Both sensitivity and pre-specified subgroup analyses yield similar results. Among patients with high adherence to AOMs, the increased risk of subsequent fracture-related hospitalization among very late users was profound (HR = 2.56, 95% CI 1.41–4.64). Conclusion Timing of AOMs initiation was significantly associated with age, index year, index hospital length of stay as well as the accreditation level and geographic region of index hospital. After adjusting factors associated with timing of AOMs initiation and patients' adherence, the anti-fracture benefit of AOMs still depends crucially on the timely initiation of AOMs.

Multitarget agents simultaneously trigger molecules in functionally complementary pathways, and are therefore considered to have potential in effectively treating Alzheimer's disease (AD), which has a complex pathogenetic mechanism. In this study, the HDAC inhibitor core is incorporated into the acetylcholine esterase (ACE) inhibitor acridine-derived moiety and resulted in compounds that exhibited higher class IIa HDAC (4, 5, 7, and 9)- and class IIb HDAC6-inhibiting activity when compared to the pan-HDAC inhibitor SAHA in clinical practice. One of these compounds, 11b, displayed greater selectivity toward HDAC6 than other isoform enzymes. In contrast, the activity of compound 6a was selective toward class IIa HDAC and HDAC6. These two compounds exhibited strong activity against Aβ-aggregation as well as significantly disrupted Aβ-oligomer. Additionally, 11b and 6a strongly inhibited AChE. These experimental findings demonstrate that compounds 11b and 6a are HDAC-Aβ-aggregation-AChE inhibitors. Notably, they can enhance neurite outgrowth, but with no significant neurotoxicity. Further biological evaluation revealed the various cellular effects of multitarget compounds 11b and 6a, which have the potential to treat AD.

Background We investigated whether prior stain use before admission for a first-attack AP would reduce the severity and mortality rate of a first-attack of AP with a dose–response relationship. Methods We conducted a retrospective cohort study from a tertiary medical center's database in Taiwan. We evaluated the dose–response relationship between statin use and the first-attack of AP by defining the daily dose (DDD). The cumulative DDD (cDDD) was calculated as the sum of the dispensed DDD of any specific statin. The outcome measures in our study included the hospital mortality rate, duration of hospitalization, Ranson's score, computed tomography severity index (CTSI), and C-reactive protein (CRP) level. Results In our study, we enrolled 31 patients in statin group and 63 matched patients in control group. In the univariate analysis there was no significant difference between them with regard to the outcomes except the CTSI and serum calcium concentration. According to multivariate analysis the serum calcium concentration was significantly higher in the statin group, and the CTSI was lower in the statin group. In subgroup analysis we divided the statin group into two groups according to the cDDDs ( 365 days) and the results showed no significance in the demographic data, overall mortality rate, hospitalization days, CRP level, Ranson's score, or CTSI. Conclusion Our study rejected the hypothesis that statins have beneficial effects on the clinical outcomes of patients with a first-attack of AP. However we demonstrated that statins have a positive effect on the CTSI.

Antioxidative activities were found in the culture supernatant of Serratia ureilytica TKU013 with squid pen as the sole carbon/nitrogen source. The 4th day supernatant showed the strongest antioxidant activities and the highest total phenolic content. The supernatant was further purified by liquid–liquid partition, and it was found that the ethyl acetate-soluble (EA) extract exhibited the strongest antioxidant activity in a DPPH radical-scavenging assay and this was compared with the positive control, α-tocopherol. This extract was further divided into eight fractions, designated as F1–F8, by silica gel liquid chromatography. In most cases, F4 and F8 were found to possess the strongest antioxidative activities. Significant associations between the antioxidant potency and the total phenolic content, as well as between the antioxidant potency and free amino groups, were found for the supernatant, extract, and fractions. With this method, squid pen waste can be utilized and has potential in the production of functional foods.