Search

Understanding the social-psychological processes that characterize communities’ reactions to a pandemic is the first step toward formulating risk communications that can lead to better health outcomes. This study examines comments on Facebook pages of five Singapore media outlets to understand what topics are being discussed by the public in reaction to the implemented precautionary measures in Singapore so as to infer their psychological concerns. Using Anchored Correlation Explanation as a topic modelling technique, this study examines around 10,000 comments and identifies 21 topics that are discussed. The 21 topics were categorized and organized into seven broad themes of psychological concerns. Implications for theory and practice are then discussed.

Pseudomonas aeruginosa is a clinically important pathogen implicated in many hospital-acquired infections. Its propensity to acquire broad-spectrum resistance has earned the organism its status as a severe public health threat requiring urgent control measures. While whole-genome sequencing-based genomic surveillance provides a means to track antimicrobial resistance, its use in molecular epidemiological surveys of P. aeruginosa remains limited, especially in the Southeast Asian region. We sequenced the whole genomes of 222 carbapenem-non-susceptible P. aeruginosa (CNPA) isolates collected in 2006–2020 at the largest public acute care hospital in Singapore. Antimicrobial susceptibilities were determined using broth microdilution. Clonal relatedness, multi-locus sequence types, and antimicrobial resistance determinants (acquired and chromosomal) were determined. In this study, CNPA exhibited broad-spectrum resistance (87.8% multi-drug resistance), retaining susceptibility only to polymyxin B (95.0%) and amikacin (55.0%). Carbapenemases were detected in 51.4% of the isolates, where IMP and NDM metallo-β-lactamases were the most frequent. Carbapenem resistance was also likely associated with OprD alterations or efflux mechanisms (ArmZ/NalD mutations), which occurred in strains with or without carbapenemases. The population of CNPA in the hospital was diverse; the 222 isolates grouped into 68 sequence types (ST), which included various high-risk clones. We detected an emerging clone, the NDM-1-producing ST308, in addition to the global high-risk ST235 clone which was the predominant clone in our population. Our results thus provide a “snapshot” of the circulating lineages of CNPA locally and the prevailing genetic mechanisms contributing to carbapenem resistance. This database also serves as the baseline for future prospective surveillance studies.

MotivationSpatially resolved transcriptomics (SRT) technologies have been developed to simultaneously profile gene expression while retaining physical information. To explore differentially expressed genes using SRT in the context of various conditions, statistical methods are needed to perform spatial differential expression analysis.ResultsWe propose that a new probabilistic framework, spatialDEG, can perform differential expression analysis by leveraging spatial information on gene expression with spatial information. SpatialDEG utilizes the average information algorithm and can be scalable to tens of thousands of genes. Comprehensive simulations demonstrated that spatialDEG can identify genes differentially expressed in tissues across different conditions with a controlled type-I error rate. We further applied spatialDEG to analyze datasets for human dorsolateral prefrontal cortex and mouse whole liver.AvailabilityThe R package spatialDEG can be downloaded from https://github.com/Shufeyangyi2015310117/spatialDEG.

Giant cells (GC) are a poorly understood subset of tumor cells that have been increasingly recognized as a potential contributor to tumor heterogeneity and treatment resistance. We aimed to characterize the biological and clinical significance of GC in angiosarcoma, an aggressive rare cancer of endothelial origin. Archival angiosarcoma samples were examined for the presence of GC and compared with clinicopathological as well as NanoString gene expression data. GC were examined in angiosarcoma cell lines MOLAS and ISOHAS using conventional and electron microscopy, single cell whole genome profiling, and other assays. In the cell lines, GC represented a rare population of mitotically active, non–senescent CD31+ cells, and shared similar genomic profiles with regular‐sized cells, consistent with a malignant endothelial phenotype. GC remained viable and persisted in culture following exposure to paclitaxel and doxorubicin. In patient samples, GC were present in 24 of 58 (41.4%) cases. GC was correlated with poorer responses to chemotherapy (25.0% vs 73.3%, P = 0.0213) and independently contributed to worse overall survival outcomes (hazard ratio 2.20, 95% confidence interval 1.17‐4.15, P = 0.0142). NanoString profiling revealed overexpression of genes, including COL11A1, STC1, and ERO1A, accompanied by upregulation of immune‐related metabolic stress and metastasis/matrix remodeling pathways in GC‐containing tumors. In conclusion, GC may contribute to chemoresistance and poor prognosis in angiosarcoma., This paper aims to characterize the biological and clinical significance of bizarre giant cells (GC) in angiosarcoma. GC in angiosarcoma cell lines demonstrated relative chemoresistance. GC positivity in patient samples was associated with poorer response to chemotherapy and poorer overall survival.

Breast fibroepithelial lesions (FELs) encompass the common fibroadenoma (FA) and relatively rare phyllodes tumour (PT); the latter entity is usually classified as benign, borderline or malignant. Intratumoural heterogeneity is frequently present in these tumours, making accurate histologic evaluation challenging. Despite their rarity, PTs are an important clinical problem due to their propensity for recurrence and, in the case of malignant PT, metastasis. Surgical excision is the mainstay of management. Recent work has uncovered myriad genetic alterations in breast FELs. In this study, exome sequencing was performed on seven cases of morphologically heterogeneous breast FELs, including FAs, PTs of all grades, and a case of metaplastic spindle cell carcinoma arising in PT, in order to elucidate their intratumoural genetic repertoire. Gene mutations identified encompassed cell signalling, tumour suppressor, DNA repair and cell cycle regulating pathways. Mutations common to multiple tumour regions generally showed higher variant allele frequency. Frequent mutations included MED12, TP53, RARA and PIK3CA. Histological observations of increased cellular density and pleomorphism correlated with mutational burden. Phylogenetic analyses revealed disparate pathways of possible tumour progression. In summary, histological heterogeneity correlated with genetic changes in breast FELs.

Malignant phyllodes tumors (PT) are rare aggressive fibroepithelial neoplasms with high metastatic potential and lack effective therapy. We established a patient-derived xenograft (PDX) and cell line model (designated MPT-S1) of malignant PT which demonstrated clinical response to pazopanib. Whole exome sequencing identified somatic mutations in TP53, RB1, MED12, and KMT2D. Immunohistochemistry and genomic profiles of the tumor, PDX and cell line were concordant. In keeping with clinical observation, pazopanib reduced cell viability in a dose-dependent manner and evoked apoptosis, and led to significant abrogation of in vivo tumor growth. Whole transcriptomic analysis revealed that pazopanib decreased expression of genes involved in oncogenic and apoptosis signaling. We also observed decreased expression of ENPP1, with known roles in cancer invasion and metastasis, as well as STING pathway upregulation. Accordingly, pazopanib induced micronuclei formation, and evoked phospho-TBK1 and PD-L1 expression. In an additional cohort of malignant PT (n = 14), six (42.9%) showed comparable or higher levels of ENPP1 relative to MPT-S1, highlighting its potential role as a therapeutic target. In conclusion, we established MPT-S1, a new PDX and cell line model, and provided evidence for the clinical efficacy of pazopanib in malignant PT.

Increasing resistance to polymyxin, a last-line antibiotic, is a growing public health concern worldwide. The primary objective of this study was to identify predictors for the isolation of polymyxin-resistant (PR) carbapenem-resistant Enterobacteriaceae (CRE) among hospitalized patients. The secondary objective was to describe the clinical outcomes of patients with PR-CRE infections. A retrospective case–control study including patients admitted to Singapore General Hospital between June 2012 and June 2016 was conducted. Cases were defined as patients who had clinical cultures from which a PR-CRE was isolated. Controls were randomly selected from patients with polymyxin-susceptible (PS) CRE admitted during the same period, and frequency-matched to site of isolation. We included 37 PR cases and 111 PS controls. Polymyxin resistance was detected predominantly in Enterobacter spp. (54.1%) and Klebsiella pneumoniae (43.2%). Multilocus sequence typing showed little clonal relatedness among the isolates. mcr-1 was detected in two PR-CRE isolates. Multivariable analyses showed that PR-CRE isolation was associated with prior polymyxins (adjusted odds ratio (OR), 21.31; 95% confidence interval (CI), 3.04–150.96) and carbapenem exposures (OR 3.74; CI 1.13–12.44), when adjusted for time at risk and bacteria species. In PR-CRE patients with infections, the 30-day all-cause in-hospital mortality was 50.0% as compared to 38.1% in patients with PS-CRE (P = 0.346). Prior polymyxin and carbapenem exposures were independent risk factors for isolation of PR-CRE. Outcomes of PR-CRE and PS-CRE infections were similar in this study.

Pseudomonas aeruginosa infection is one of the most difficult health care-associated infections to treat due to the ability of the organism to acquire a multitude of resistance mechanisms and express the multidrug resistance phenotype. Ceftolozane/tazobactam (C/T), a novel β-lactam/β-lactamase inhibitor combination, addresses an unmet medical need in patients with these multidrug-resistant P. aeruginosa infections., This study established the in vitro activity of ceftolozane/tazobactam (C/T) and its genotypic resistance mechanisms by whole-genome sequencing (WGS) in 195 carbapenem-nonsusceptible Pseudomonas aeruginosa (CNSPA) clinical isolates recovered from Singapore between 2009 and 2020. C/T susceptibility rates were low, at 37.9%. Cross-resistance to ceftazidime/avibactam was observed, although susceptibility to the agent was slightly higher, at 41.0%. Whole-genome sequencing revealed that C/T resistance was largely mediated by the presence of horizontally acquired β-lactamases, especially metallo-β-lactamases. These were primarily disseminated in well-recognized high-risk clones belonging to sequence types (ST) 235, 308, and 179. C/T resistance was also observed in several non-carbapenemase-producing isolates, in which resistance was likely mediated by β-lactamases and, to a smaller extent, mutations in AmpC-related genes. There was no obvious mechanism of resistance observed in five isolates. The high C/T resistance highlights the limited utility of the agent as an empirical agent in our setting. Knowledge of local molecular epidemiology is crucial in determining the potential of therapy with novel agents. IMPORTANCE Pseudomonas aeruginosa infection is one of the most difficult health care-associated infections to treat due to the ability of the organism to acquire a multitude of resistance mechanisms and express the multidrug resistance phenotype. Ceftolozane/tazobactam (C/T), a novel β-lactam/β-lactamase inhibitor combination, addresses an unmet medical need in patients with these multidrug-resistant P. aeruginosa infections. Our findings demonstrate geographical variation in C/T susceptibility owing to the distinct local molecular epidemiology. This study adds on to the growing knowledge of C/T resistance, particularly mutational resistance, and will aid in the design of future β-lactams and β-lactamase inhibitors. WGS proved to be a useful tool to understand the P. aeruginosa resistome and its contribution to emerging resistance in novel antimicrobial agents.

Angiosarcomas are a rare subtype of soft-tissue sarcomas which exhibit aggressive clinical phenotypes with limited treatment options and poor outcomes. In this study, we investigated the clinical relevance of the peripheral blood neutrophil-to-lymphocyte ratio (NLR) as a marker of systemic immune response, as well as its correlation with intra-tumoral immune profiles in a subgroup of cases (n = 35) using the NanoString PanCancer IO360 panel and multiplex immunohistochemistry. In the overall cohort (n = 150), angiosarcomas of the head and neck (AS-HN) comprised most cases (58.7%) and median overall survival (OS) was 1.1 year. NLR, classified as high in 78 of 112 (70%) evaluable patients, was independently correlated with worse OS (HR 1.84, 95%CI 1.18–2.87, p = 0.0073). Peripheral blood NLR was positively correlated with intra-tumoral NLR (tNLR) (Spearman’s rho 0.450, p = 0.0067). Visualization of tumor-infiltrating immune cells confirmed that tNLR scores correlated directly with both neutrophil (CD15+ cells, rho 0.398, p = 0.0198) and macrophage (CD68+ cells, rho 0.515, p = 0.0018) cell counts. Interestingly, tNLR correlated positively with oncogenic pathway scores including angiogenesis, matrix remodeling and metastasis, and cytokine and chemokine signaling, as well as myeloid compartment scores (all p

Breast fibroepithelial lesions are biphasic tumors which comprise the common benign fibroadenomas (FAs) and the rarer phyllodes tumors (PTs). This study analyzed 262 (42%) conventional FAs, 45 (7%) cellular FAs, and 321 (51%) benign PTs contributed by the International Fibroepithelial Consortium, using a previously curated 16 gene panel. Benign PTs were found to possess a higher number of mutations, and higher rates of cancer driver gene alterations than both groups of FAs, in particular MED12, TERT promoter, RARA, FLNA, SETD2, RB1, and EGFR. Cases with MED12 mutations were also more likely to have TERT promoter, RARA, SETD2, and EGFR. There were no significant differences detected between conventional FAs and cellular FAs, except for PIK3CA and MAP3K1. TERT promoter alterations were most optimal in discriminating between FAs and benign PTs. Our study affirms the role of sequencing and key mutations that may assist in refining diagnoses of these lesions.

Peritoneal carcinomatosis (PC) present a ubiquitous clinical conundrum in all intra-abdominal malignancies. Via functional and transcriptomic experiments of ascites-treated PC cells, we identify STAT3 as a key signaling pathway. Integrative analysis of publicly available databases and correlation with clinical cohorts (n = 7,359) reveal putative clinically significant activating ligands of STAT3 signaling. We further validate a 3-biomarker prognostic panel in ascites independent of clinical covariates in a prospective study (n = 149). Via single-cell sequencing experiments, we uncover that PAI-1, a key component of the prognostic biomarker panel, is largely secreted by fibroblasts and mesothelial cells. Molecular stratification of ascites using PAI-1 levels and STAT3 activation in ascites-treated cells highlight a therapeutic opportunity based on a phenomenon of paracrine addiction. These results are recapitulated in patient-derived ascites-dependent xenografts. Here, we demonstrate therapeutic proof of concept of direct ligand inhibition of a prognostic target within an enclosed biological space.

Rhein, an anthraquinone drug, is a widely used traditional Chinese medicine. Rhein is a major bioactive metabolite of diacerein which has been approved for treating osteoarthritis with a good safety profile in humans. Gouty arthritis is an inflammatory disease characterized by urate crystal-induced NLRP3 inflammasome activation with up-regulated caspase-1 protease and IL-1[Formula: see text] in macrophages. Inhibition of the NLRP3 inflammasome formation has been considered as a potential therapeutic avenue for treating or preventing many inflammatory diseases. This study aimed to evaluate the anti-inflammatory effects of rhein on gouty arthritis. Rhein within the physiological levels of humans showed no toxicity on the cell viability and differentiation, but significantly decreased the production of IL-1[Formula: see text], TNF-[Formula: see text] and caspase-1 protease in urate crystal-activated macrophages. Compared to medium controls, rhein at the therapeutic concentration (2.5[Formula: see text][Formula: see text]g/mL) effectively inhibited IL-1[Formula: see text] production by 47% ([Formula: see text]). Rhein did not affect the mRNA levels of CASP1, NLRP3 and ASC, but suppressed the protein expression and enzyme activity of caspase-1. Immunofluorescence confocal microscopy further revealed that rhein suppressed the aggregation of ASC speck and inhibited the formation of NLRP3 inflammasome. Rhein of 5[Formula: see text][Formula: see text]g/mL significantly decreased the ASC speck to 36% ([Formula: see text]), and reduced the NLRP3 aggregates to 37.5% ([Formula: see text]). Our data demonstrate that rhein possesses pharmacological activity to suppress caspase-1 protease activity and IL-1[Formula: see text] production by interfering with the formation of NLRP3 multiprotein complex. These results suggest that rhein has therapeutic potential for treating NLRP3 inflammasome-mediated diseases such as gouty arthritis.

The original article [1] contains an error whereby the author, Pui Lai Rachel Ee’s name is incorrectly presented.

A majority of breast cancer cases are positive for the estrogen receptor (ER), which means that they can respond to the estrogen hormone to achieve growth. Hence, the ER signaling pathway has been extensively targeted in pharmaceutical research and development in order to suppress tumor growth. However, prevalent hormone therapy and targeted therapy often become ineffective as cancer cells ultimately develop resistance, suggesting that there could be unidentified signaling molecules and events that regulate breast cancer growth. Notably, recent studies have uncovered that Piwi‑like (Piwil) proteins, which were initially found in germline cells, are expressed in a wide spectrum of human cancers, including breast cancers. Although Piwil proteins have been well established to silence retrotransposons and to promote heterochromatin formation in germline cells, their somatic functions in cancer cells remain largely unknown. In the present study, we profiled the expression of four Piwi homologs in an ER‑positive breast cancer cell line, MCF‑7, and found that only Piwil4 was upregulated by 17β‑estradiol treatment. Notably, Piwil4 upregulation was not observed in an ER‑positive but non‑tumorigenic breast cancer cell line, MCF‑12A. In addition, the induced expression of Piwil4 was dependent on estrogen/ERα signaling. To explore the biological significance of Piwil4 in breast cancer growth, we knocked down Piwil4 with multiple siRNAs and observed the suppressed expression of some canonical targets of ER. The knockdown of Piwil4 expression also decreased the migration and invasion capabilities of MCF‑7 cells. Furthermore, the loss‑of‑function of Piwil4 reduced the motility of MCF‑7 cells in wound‑healing assays, which could be associated to decreased expression of vimentin and N‑cadherin. Collectively, these findings revealed that Piwil4 is a novel regulator of ER signaling that could be targeted to inhibit breast cancer growth and migration.

Background Antifungal resistance rates are increasing. We investigated the mechanisms of azole resistance of Candida spp. bloodstream isolates obtained from a surveillance study conducted between 2012 and 2015. Methods Twenty-six azole non-susceptible Candida spp. clinical isolates were investigated. Antifungal susceptibilities were determined using the Sensititre YeastOne® YO10 panel. The ERG11 gene was amplified and sequenced to identify amino acid polymorphisms, while real-time PCR was utilised to investigate the expression levels of ERG11, CDR1, CDR2 and MDR1. Results Azole cross-resistance was detected in all except two isolates. Amino acid substitutions (A114S, Y257H, E266D, and V488I) were observed in all four C. albicans tested. Of the 17 C. tropicalis isolates, eight (47%) had ERG11 substitutions, of which concurrent observation of Y132F and S154F was the most common. A novel substitution (I166S) was detected in two of the five C. glabrata isolates. Expression levels of the various genes differed between the species but CDR1 and CDR2 overexpression appeared to be more prominent in C. glabrata. Conclusions There was interplay of various different mechanisms, including mechanisms which were not studied here, responsible for azole resistance in Candida spp in our study.

A series of new imidazolium salts was synthesized by simple quaternization reactions of 1-benzyl-1H-imidazole or 1-benzyl-2-methyl-1H-imidazole and their derivatives with 2-chloro-N-(pyridin-2-ylmethyl)acetamide. These resulting imidazolium salts were successfully employed as ligand precursors for the syntheses of novel palladium(II) complexes bearing tridentate ligands of N-heterocyclic carbene, amidate, and pyridine donor moieties. Simple tuning of the reaction conditions allowed selective coordination of the N-heterocyclic carbene moiety in either “normal” or “abnormal” binding modes. An isomeric pair of palladium complexes with “normal” and “abnormal” N-heterocyclic carbenes was successfully characterized by single-crystal X-ray diffraction studies. Theoretical calculations indicated that the palladium complex with “normal” NHC coordination was more thermally stable than its isomeric complex with “abnormal” NHC binding. The potential of these two sets of palladium complexes as anticancer drugs was eva...

Background and rationale. The control of Endothelin-1 (ET-1)-mediated intrahepatic vasoconstriction in cirrhosis is beneficial for the alleviation of relevant complications. Cirrhosis is accompanied by hypogonadism and altered sex hormone status. Besides, sex hormones have vasoactive effects, but it is unknown if they influence vascular function in cirrhosis. This study aimed to investigate the roles of sex hormones in hepatic vascular reactions to ET-1 in cirrhosis. Liver cirrhosis was induced in Spraque-Dawley male and female rats with common bile duct ligation (BDL). Sham-operated (Sham) rats were controls. On the 43rd day after operations, intrahepatic vascular concentration-response curves to ET-1 were obtained with the following preincubatioins: 1) vehicle; 2) 17β-estradiol; 3) progesterone; 4) testosterone. Livers from sham and BDL rats were dissected for real-time polymerase chain reaction analysis of estrogen, progesterone and testosterone receptors. Results. Compared with sham males perfused with vehicle, sham females presented higher perfusion pressure changes to ET-1 which was reversed only by 17β-estradiol. In cirrhosis, compared with males, 17β-estradiol no longer attenuated vascular responsiveness to ET-1 in females. In females, BDL rats had lower hepatic estrogen receptor α(ERα) mRNA expression than that in sham rats. Conclusions. The sham females showed a stronger intrahepatic vascular constrictive effect to ET-1 than sham males, which could be reversed by 17β-estradiol. However, the influence of 17β-estradiol was lost in cirrhotic females, which may be attributed, at least partly, to intrahepatic ERα down-regulation in females with cirrhosis.

Three new two-dimensional coordination polymers were constructed from 2,6-bis(imidazole-1-yl)pyridine (2.6-bip), terephthalic acid (1,4-bdcH 2 ), and M(NO 3 )∙nH 2 O (M = Co, Cd). [M(2,6-bip)(1,4-bdc)] ( 1 : M = Co; 2 : M = Cd) were prepared under hydrothermal condition, whereas [Cd(2,6-bip)(1,4-bdc)∙ x DMF] ( 3 ) was obtained under solvothermal condition in DMF solvent. Single-crystal X-ray analyses revealed the first example of a 2D 4-connected net of 6 6 topology in 1 and 2 and a rare 2D 4,5-connected net of 4,5 L20 topology in 3 . All these complexes were thermally robust and emissive in solid-states. This work confirmed the versatility of using hingelike 2,6-bip as a linker and the importance of solvent effect in the process of framework formation.

Background and Aim Hypo-perfusion resulting from intense renal vasoconstriction is traditionally contributed to renal dysfunction in advanced liver disease, although cumulative studies demonstrated renal vasodilatation with impaired vascular contractility to endogenous vasoconstrictors in portal hypertension and compensated liver cirrhosis. The pathophysiology of altered renal hemodynamics remains unclear. This study, using a rat model of portal hypertension with superimposed endotoxemia, was designed to delineate the evolution of renal vascular reactivity and vaso-regulatory gene expression during liver disease progression. Methods Rats were randomized into sham surgery (SHAM) or partial portal vein ligation (PVL). Endotoxemia was induced by intraperitoneal injection of lipopolysaccharide (LPS) on the seventh day following surgery. Isolated kidney perfusion was performed at 0.5 h or 5 h after LPS to evaluate renal vascular response to endothelin-1. Results In contrast to impaired vascular contractility of SHAM rats, PVL rats displayed enhanced renal vascular reactivity to endothelin-1 at 5 h following endotoxemia. There were extensive upregulations of inducible nitric oxide synthase in kidney tissues of endotoxemic rats. The changes of renal endothelin receptor type A (ETA) level paralleled with the changes of renal vascular reactivity in LPS-treated rats. Compared with SHAM rats, PVL rats showed increased renal ETA and phosphorylated extracellular-signal-regulated kinases 1/2 (p-ERK1/2) at 5 h after LPS. Conclusion LPS-induced systemic hypotension induces a paradoxical change of renal vascular response to endothelin-1 between SHAM and PVL rats. LPS-induced renal vascular hyperreactivity in PVL rats was associated with upregulation of renal ETA and subsequent activation of ERK1/2 signaling.

A series of new imidazolium chlorides were straightforwardly prepared from the reactions between chloroacetone and imidazole derivatives. Deprotonation of the methylene proton next to the ketone group in these salts by pyridine led to the formation of a monodentate ligand that coordinated to palladium, readily forming zwitterionic anionic palladium pyridine complexes bearing a formal positive charge on the ligand ancillary. The pyridine ligand in the zwitterionic complexes can be facilely replaced by phosphine ligands. Seven of these new complexes were successfully characterized by X-ray crystallography. The zwitterionic phosphine complexes were highly efficient in catalyzing room-temperature Suzuki–Miyaura reactions between sterically hindered aryl chlorides and arylboronic acids in an aqueous medium.

Solvothermal syntheses involving the hybrid ligands {3-pyridin-3-ylimidazo[1,2-a]pyridine (L1) and 3-pyridin-4-ylimidazo[1,2-a]pyridine (L2)}, aromatic polycarboxylates [1,4-benzenedicarboxylate (1,4-bdc), 1,3-benzenedicarboxylate (1,3-bdc), and 1,3,5-benzenetricarboxylate (1,3,5-btc)], and transition metal ions [Ni(II) and Zn(II) ions] afforded five new coordination polymers, namely, [Ni(1,4-bdc)(L1)(H2O)2]n (1), [Ni2(1,3-bdc)2(L1)2(H2O)]n (2), [Zn2(1,4-bdc)1.5(L1)(OH)]n (3), and [Zn2(1,3,5-btc)(L1)O0.5(H2O)0.5·0.5H2O]n (4), and [Zn2(1,3,5-btc)(L2)(OCOH)(H2O)]n (5). A diversity of net topologies was observed including a rare 2D 4-connected net with the point symbol of (44·63·8) in 1, a dia net in 2, a twofold interpenetrating pcu net in 3, a rare 3D (3,8)-connected binodal 3,8T35 net in 4, and sra and rtl nets in 5. Four different secondary building units were involved in the construction of the 3D nets. The three Zn(II) complexes exhibit photoluminescence.

Endothelin-1 (ET-1) exerts vasoconstrictive effect on portal-systemic collateral vascular bed of portal hypertensive rats. Statins are lipid-lowering agents with nitric oxide (NO)-related vasodilatory effects. Considering NO-associated vascular hyporesponsiveness to vasoconstrictors and shunting formation in portal hypertension, this study investigated the effects of simvastatin on 1) the portal-systemic collateral vascular responsiveness to ET-1 and 2) the portal-systemic shunting degree.Portal hypertension was induced by partial portal vein ligation (PVL) in Sprague-Dawley rats. Simvastatin (20 mg/kg/day) or distilled water (control) was randomly administered by oral gavage since 2 days prior to until 7 days after PVL. Systemic and portal hemodynamics were measured on the 8th day. In another series, collateral perfusion with Krebs solution at different flow rates was performed to get flow-pressure curves which serve as an index of shunting degree. To survey the direct vascular effect, PVL rats randomly underwent preincubation with 1) Krebs solution, that is, the control group; or Krebs solution plus 2) simvastatin; 3) simvastatin + N (ω)-nitro-L-arginine (NNA, a NO synthase inhibitor); 4) simvastatin + indomethacin (a cyclooxygenase inhibitor), followed by ET-1 to evaluate the collateral vascular responsiveness.Chronic simvastatin treatment significantly reduced portal pressure. The flow-pressure curves were similar between two groups. Simvastatin preincubation reduced collateral perfusion pressure changes to ET-1 (p0.05), which were partially reversed by NNA (p0.05), but not by indomethacin. Conclusions. Chronic simvastatin treatment significantly improved portal hypertension. The effect was at least partially exerted by decreased portal-systemic collateral vascular resistance through NO-mediated vascular hyporesponsiveness. The severity of portal-systemic collaterals was not influenced by simvastatin.

Background Candidemia is a common cause of nosocomial bloodstream infections, resulting in high morbidity and mortality. This study was conducted to describe the epidemiology, species distribution, antifungal susceptibility patterns and outcomes of candidemia in a large regional tertiary referral hospital. Methods A retrospective surveillance study of patients with candidemia was conducted at Singapore General Hospital between July 2012 and December 2015. In addition, incidence densities and species distribution of candidemia episodes were analysed from 2008 to 2015. Results In the period of 2012 to 2015, 261 candidemia episodes were identified. The overall incidence was 0.14/1000 inpatient-days. C. glabrata (31.4%), C. tropicalis (29.9%), and C. albicans (23.8%) were most commonly isolated. The incidence of C. glabrata significantly increased from 2008 to 2015 (Coefficient 0.004, confidence interval 0–0.007, p = 0.04). Fluconazole resistance was detected primarily in C. tropicalis (16.7%) and C. glabrata (7.2%). fks mutations were identified in one C. albicans and one C. tropicalis. Candidemia episodes caused by C. tropicalis were more commonly encountered in patients with haematological malignancies (p = 0.01), neutropenia (p

Angiogenesis in liver cirrhosis leads to splanchnic hyperemia, increased portal inflow, and portosystemic collaterals formation, which may induce lethal complications, such as gastroesophageal variceal hemorrhage and hepatic encephalopathy. Cannabinoids (CBs) inhibit angiogenesis, but the relevant influences in cirrhosis are unknown. In this study, Spraque-Dawley rats received common bile duct ligation (BDL) to induce cirrhosis. BDL rats received vehicle, arachidonyl-2-chloroethylamide (cannabinoid receptor type 1 [CB1] agonist), JWH-015 (cannabinoid receptor type 2 [CB2] agonist), and AM630 (CB2 antagonist) from days 35 to 42 days after BDL. On the 43rd day, hemodynamics, presence of CB receptors, severity of portosystemic shunting, mesenteric vascular density, vascular endothelial growth factor (VEGF), VEGFR-1, VEGFR-2, phospho-VEGFR-2, cyclooxygenase (COX)-1, COX-2, and endothelial nitric oxide synthase (eNOS) expressions as well as plasma VEGF levels were evaluated. Results showed that CB1 and CB2 receptors were present in left adrenal veins of sham rats, splenorenal shunts (the most prominent intraabdominal shunts) of BDL rats, and mesentery of sham and BDL rats. CB2 receptor was up-regulated in splenorenal shunts of BDL rats. Both acute and chronic JWH-015 treatment reduced portal pressure and superior mesenteric arterial blood flow. Compared with vehicle, JWH-015 significantly alleviated portosystemic shunting and mesenteric vascular density in BDL rats, but not in sham rats. The concomitant use of JWH-015 and AM630 abolished JWH-015 effects. JWH-133, another CB2 agonist, mimicked the JWH-015 effects. JWH-015 decreased mesenteric COX-1, COX-2 messenger RNA expressions, and COX-1, COX-2, eNOS protein expressions. Furthermore, JWH-015 decreased intrahepatic angiogenesis and fibrosis. Conclusions :C B 2 agonist alleviates portal hypertension (PH), severity of portosystemic collaterals and mesenteric angiogenesis, intrahepatic angiogenesis, and fibrosis in cirrhotic rats. The mechanism is, at least partly, through COX and NOS down-regulation. CBs may be targeted in the control of PH and portosystemic collaterals. (HEPATOLOGY 2012;56:248-258)

Background: Cytokines are involved in liver injury and cirrhosis and systemic and hepatic cytokine levels may help predict cirrhosis evolution. However, the relevant survey has not been performed. Methods: Male Sprague-Dawley rats (240e270 g) received either common bile duct ligation (BDL, animal model of cholestatic liver injury) or sham operation (control). Five rats were sacrificed and liver and serum were collected from each in weeks 1, 2, 4, 6, 8 and 10 after surgery. Hepatic expression of interferon-g (IFN-g), tumor necrosis factor-a (TNF-a), interleukin-10 (IL-10) and transforming growth factor-b (TGF-b) were analyzed by immunohistochemial staining. The corresponding serum levels were measured by ELISA. Results: Compared to the corresponding sham groups, hepatic expression of these cytokines in BDL rats was significantly and progressively enhanced during cirrhosis development. However, serum IFN-g levels of BDL rats did not change significantly. Serum TNF-a of BDL rats increased gradually and reached a peak in week 6. Serum TGF-b level was elevated up to week 8, whereas IL-10 level decreased progressively until week 6. Conclusion: Cirrhosis development in BDL rats is associated with progressively enhanced expression of hepatic pro-inflammatory and antiinflammatory cytokines, which is not in accord with the corresponding serum concentration. The circulating cytokine concentration may not totally reflect the hepatic expression level throughout the development of cirrhosis. Copyright 2011 Elsevier Taiwan LLC and the Chinese Medical Association. All rights reserved.