Targeted Isolation of Antiviral Labdane Diterpenes from the Bark of Neo-uvaria foetida (Annonaceae) using LC-MS/MS-Based Molecular Networking.

In the search of new inhibitors for human coronavirus (HCoV), we screened extracts of endemic Annonaceae plants on an assay using a cellular model of Huh-7 cells infected with the human alphacoronavirus HCoV-229E. The EtOAc bark extract of the rare Southeast Asian plant Neo-uvaria foetida exhibited inhibition of HCoV-229E and SARS-CoV-2 viruses with IC50 values of 3.8 and 7.8 µg/mL, respectively. Using LC-MS/MS and molecular networking analysis guided isolation, we discovered two new labdane-type diterpenoids, 8-epi-acuminolide (1) and foetidalabdane A (4), and three known labdane diterpenoids, acuminolide (2), 17-O-acetylacuminolide (3), and spiroacuminolide (5). A new norlabdane diterpene, 16-foetinorlabdoic acid (6), was also isolated and identified. Excluding compounds 5 and 6, all other metabolites were active against the virus HCoV-229E. Terpenoids 1 and 4 presented antiviral activity against SARS-CoV-2 with IC50 values of 63.3 and 93.5 µM, respectively, indicating lower potency. Additionally, virological assays demonstrated that compounds 1, 2, and 3 exert antiviral effects against Zika virus by specifically interfering with the late stage of its infectious cycle with IC50 values of 76.0, 31.9, and 14.9 µM, respectively.

Efficacy of influenza vaccine (Fluvax) in cancer patients on treatment: a prospective single arm, open-label study.

PURPOSE: Influenza virus infection has significant morbidity and mortality in patients with medical co-morbidities who are also immunosuppressed. The efficacy of the seasonal influenza vaccine has not been well studied in patients receiving chemotherapy. We assessed the efficacy of seasonal influenza vaccine in patients with non-haematological malignancy on active treatment (chemotherapy and targeted therapy). METHODS: A prospective single arm, open label study with 53 patients with non-haematological cancers recruited during the 2011 and 2012 influenza seasons. Participants had one dose of 2011/2012 trivalent vaccine containing strains A/California/7/2009(H1N1), A/Perth/16/2009 (H3N2) and B/Brisbane/60/2008 (Fluvax) prior to or in-between treatment cycles. Haemagglutination inhibition antibody (HIA) titres in serum were measured at baseline 3, 6 and 24 weeks. Primary endpoint: seroconversion rate (SCR) at 3 weeks. Secondary endpoints: late SCR at 6 weeks. rate of sustained sero-protection titres (SPR) at 24 weeks. Seroconversion was defined as postvaccination ≥ 4-fold increase in HIA titre and sero-protection defined as a HIA ≥ 1:40. RESULTS: The SCR at 3 weeks were 35%, 30% and 22.5% to the H1N1, H3N2 and B/Bris strains, respectively. There were no new cases of late SC at 6 weeks or 24 weeks. The SPR at 3 weeks were 72.5%, 65% and 40%, respectively, to H1N1, H3N2 and B/Bris. The SPR at 24 weeks to H1N1, H3N2 and B/Bris were 40%, 52.5% and 17.5%, respectively. CONCLUSIONS: Patients on various solid tumour treatments achieve sero-protection rate congruent with the general population. The sero-protection HIA titres were not sustained at 24 weeks postvaccination.

Effect of pericardial effusion on outcomes in children admitted with systemic lupus erythematosus: a multicenter retrospective cohort study from the United States.

OBJECTIVE: We sought to describe characteristics of children admitted with pericardial effusion (PCE) and systemic lupus erythematosus (SLE) and determine the association between PCE and outcomes of interest. METHODS: We performed a retrospective cohort study of the Pediatric Health Information System (PHIS). Patients were included if they were admitted to a PHIS participating hospital from 2004 to 2015 with a diagnosis of SLE and age ≤18 years. Children with congenital heart disease or who had undergone heart surgery were excluded. PCE was the primary predictor variable; multivariable analysis was used to evaluate the effect of PCE on the following outcomes: mortality, length of stay (LOS), and readmission within 30 days. RESULTS: There were 5679 admissions, of which 705 (12.4%) had PCE. Median age at admission was 15 years (interquartile range: 13-17). There were no significant differences for age or sex between patients admitted either with or without PCE. A significantly higher percentage of children in the PCE group were black compared with those without PCE (43% vs. 31%, p < 0.001). In multivariable analysis, the odds of a black patient having PCE were 1.7 higher than non-black patients ( p < 0.001). In-hospital mortality was 2.5 times higher in children with PCE compared with those without PCE ( p = 0.027). Those with PCE also had 1.5 greater odds of readmission within 30 days ( p < 0.001). PCE was not associated with increased LOS (0.99, p = 0.753). CONCLUSION: PCE is common in admissions of children with SLE. There are disproportionately more black patients with SLE affected by PCE than non-black. PCE is associated with significantly higher mortality and rates of readmission.

Successful delayed-interval delivery in the presence of clinical chorioamnionitis in the leading twin: A report of two cases.

We present two cases of diamniotic, dichorionic twin pregnancies in which after the loss of the first foetus in the setting of clinical chorioamnionitis, both pregnancies were successfully managed by delayed-interval delivery. A fourstage protocol including aspects of management in this specific setting is proposed. We consider the importance of a selection process when managing conservatively, measures to promote latency and decisions regarding delivery of the foetuses. Whilst we report successful case studies of conservative management with delayed-interval delivery, we support a cautious approach and understand that in the setting of clinical chorioamnionitis of the remaining foetus, delivery is necessary.

Impact of obstructive sleep apnea on neurological recovery after ischemic stroke: A prospective study.

OBJECTIVES: The presence of obstructive sleep apnea (OSA) has been found to adversely affect the neurological recovery after acute ischemic stroke (AIS) in previous observational studies. However, in most of these studies, diagnosis of OSA was based on oximetry data alone, raising concern in the accuracy of diagnosis as well as estimation of severity. Purpose of our study was to determine the prevalence and severity of OSA (based on polysomnography and American Association of Sleep Medicine [AASM] criteria) in patients with AIS and to compare the post-stroke neurological and functional outcome, in those with and without OSA. MATERIALS AND METHODS: A prospective single-centre study was conducted over a period of eighteen months from January 2013. The demographic and clinical data were collected, and the etiology of stroke was classified according to TOAST classification. Subsequently, all selected patients (N=99) underwent premorbid sleep status assessment by Epworth Sleepiness Scale followed by polysomnography using Resmed ApneaLink polysomnograph. Data were analyzed to find out the prevalence and severity of OSA as well as its impact on neurological recovery as assessed by National Institutes of Health Stroke Scale (NIHSS) and modified Rankin scale (mRS) at different time points, starting from admission. RESULTS: There was a high prevalence of OSA (~60%) with a quarter of them having severe OSA. The OSA group had a significantly higher mean NIHSS score at discharge (P=.002) and significantly higher mRS score (irrespective of severity of OSA) at all points of evaluation. CONCLUSION: Ischemic stroke patients with OSA tend to have poor neurological and functional recovery, across all segments of stroke and OSA severity.

Pregnancy screening prior to chemotherapy administration.

A retrospective case notes review was performed to determine compliance with screening for undetected pregnancy prior to commencement of chemotherapy at Flinders Medical Centre. All female patients aged 18-55 who commenced chemotherapy between January and December 2014 were included. During the first 12 months, for women identified as having childbearing potential, pre-chemotherapy pregnancy screening was performed only in 40% of patients under 40 years and in 20.5% of the entire age range.

Goserelin toxicities and preferences for ovarian suppression method in pre-menopausal women with breast cancer.

BACKGROUND: Goserelin, a form of medical ovarian suppression, is an effective treatment for pre-menopausal women with breast cancer (PMBC). Meta-analysis data showed that similar efficacy is achieved with medical ovarian suppression and non-pharmacological ovarian suppression (NPOS) - oophorectomy or ovarian irradiation. The acceptance rate of NPOS remains low. AIMS: This study explored the reported toxicities of PMBC women and their preferred ovarian suppression method whilst on goserelin. METHODS: A postal survey consisting of 22 study-specific questions was sent to PMBC women who received goserelin at the Flinders Medical Centre. RESULTS: Nineteen women were identified from the database; 12 versus 7 women received goserelin in the adjuvant versus metastatic setting respectively. Thirteen (68.4%) responded to the survey. Women in the adjuvant cohort were more likely to report toxicities. The most common were hot flushes (100% vs 50% P = 0.033), myalgia/arthralgia (71.4% vs 16.7%, P = 0.048) and decreased libido (57/1% vs 16.7%, P = 0.135). NPOS was recalled to be offered to five (38.5%) women, with acceptance by one BRCA2 carrier. NPOS was declined initially due to fear of procedure, surgical/anaesthetic risk, invasiveness and planned future pregnancies. If given the option, upfront oophorectomy was indicated in seven (53.8%) women due to inconveniences with monthly goserelin. CONCLUSION: Half of PMBC women indicated a preference to NPOS, but only a minority recollected NPOS being discussed. Inconvenience with monthly goserelin is the main driver toward a preference of favouring NPOS. Clarification from larger trials that research patients' decision process and preferences regarding ovarian suppression is needed to validate our findings.

Genetic characterization of the wheat association mapping initiative (WAMI) panel for dissection of complex traits in spring wheat.

KEY MESSAGE: The wheat association mapping initiative is appropriate for gene discovery without the confounding effects of phenology and plant height. The wheat association mapping initiative (WAMI) population is a set of 287 diverse advanced wheat lines with a narrow range of variation for days to heading (DH) and plant height (PH). This study aimed to characterize the WAMI and showed that this diverse panel has a favorable genetic background in which stress adaptive traits and their alleles contributing to final yield can be identified with reduced confounding major gene effects through genome-wide association studies (GWAS). Using single nucleotide polymorphism (SNP) markers, we observed lower gene diversity on the D genome, compared with the other genomes. Population structure was primarily related to the distribution of the 1B.1R rye translocation. The narrow range of variation for DH and PH in the WAMI population still entailed segregation for a few markers associated with the former traits, while Rht genes were associated with grain yield (GY). Genotype by environment (G × E) interaction for GY was primarily explained by Rht-B1, Vrn-A1 and markers on chromosomes 2D and 3A when running GWAS with genotype scores from the G × E biplot. The use of PC scores from the G × E biplot seems a promising tool to determine genes and markers associated with complex interactions across environments. The WAMI panel lends itself to GWAS for complex trait dissection by avoiding the confounding effects of DH and PH which were reduced to a minimum (using Rht-B1 and Vrn-A1 scores as covariables), with significant associations with GY on chromosomes 2D, 3A and 3B.

Delayed onset of benign pleural effusion following concurrent chemoradiotherapy for inoperable non-small-cell lung cancer.

Chronic benign pleural effusion (BPE) is a rare complication of concurrent chemoradiotherapy (CRT) for inoperable stage IIIA non-small-cell lung cancer (NSCLC). This report presents three cases of BPE, the workup to differentiate this benign condition from recurrence of cancer and recommends a pleural biopsy as part of the diagnostic process. These inflammatory exudates often remain indolent, and may not require drainage or surgical intervention. In the absence of clinical, radiological and pathological evidence of recurrent disease, we recommend clinicians manage these patients expectantly, using regular clinical assessment and imaging.

Attogram sensing of trinitrotoluene with a self-assembled molecular gelator.

Detection of explosives is of utmost importance due to the threat to human security as a result of illegal transport and terrorist activities. Trinitrotoluene (TNT) is a widely used explosive in landmines and military operations that contaminates the environment and groundwater, posing a threat to human health. Achieving the detection of explosives at a sub-femtogram level using a molecular sensor is a challenge. Herein we demonstrate that a fluorescent organogelator exhibits superior detection capability for TNT in the gel form when compared to that in the solution state. The gel when coated on disposable paper strips detects TNT at a record attogram (ag, 10(-18) g) level (∼12 ag/cm(2)) with a detection limit of 0.23 ppq. This is a simple and low-cost method for the detection of TNT on surfaces or in aqueous solutions in a contact mode, taking advantage of the unique molecular packing of an organogelator and the associated photophysical properties.

Quantitative investigations of aggregate systems.

Nanomaterials with disordered, ramified structure are increasingly being used for applications where low cost and enhanced performance are desired. A particular example is the use in printed electronics of inorganic conducting and semiconducting nanoparticles. The electrical, as well as other physical properties depend on the arrangement and connectivity of the particles in such aggregate systems. Quantification of aggregate structure and development of structure/property relationships is difficult and progress in the application of these materials in electronics has mainly been empirical. In this paper, a scaling model is used to parameterize the structure of printed electronic layers. This model has chiefly been applied to polymers but surprisingly it shows applicability to these nanolayers. Disordered structures of silicon nanoparticles forming aggregates are investigated using small angle x-ray scattering coupled with the scaling model. It is expected that predictions using these structural parameters can be made for electrical properties. The approach may have wide use in understanding and designing nano-aggregates for electronic devices.

Volume and location of the defect as predictors of speech outcome after glossectomy: correlation with a classification.

The evaluation of speech outcomes after resection and reconstruction of the oral tongue remains largely unsystematic. A cross-sectional study was performed to analyse the speech outcomes of patients who underwent curative treatment with appropriate reconstruction. Sixty-nine patients were assessed for speech intelligibility and phonetics using a validated speech intelligibility assessment tool in the local language. Volume defects were classified as class I (less than one third), II (one third to half), III (half to two-thirds), or IV (two-thirds to total glossectomy). Defect location was defined as lateral, tip, or sulcus. The χ2 test and Kruskal-Wallis test were used to test volume and location as predictors. Twenty-six patients had class I defects, 29 had class II defects, seven had class III defects, and seven had class IV defects. Twenty-two patients (31.9%) received adjuvant radiotherapy. Mean vowel, consonant, word, and paragraph intelligibility were 99.27%, 86.86%, 85.52%, and 88.72%, respectively. The incremental volume of the glossectomy defect was significantly correlated with speech intelligibility scores and phonatory alterations. In classes II and III, tip resection significantly affected interdental sounds. All patients in class III had affected alveolar and alveo-palatal sounds. The results positively corroborated the volume and location of the glossectomy defect to a classification system.

A phase I study to determine the safety, tolerability and maximum tolerated dose of green-lipped mussel (Perna canaliculus) lipid extract, in patients with advanced prostate and breast cancer.

BACKGROUND: This was a phase I trial to determine the maximum tolerated dose (MTD) of a marine lipid extract from the New Zealand green-lipped mussel (Perna canaliculus), as an inhibitor of 5- and 12-lipo-oxygenase enzymes, in patients with advanced breast and prostate cancers. PATIENTS AND METHODS: This was an open-labelled, phase I, dose-escalation study. Proprietary form of green-lipped mussel lipid extract (GLMLE), 260-mg capsule, was administered on a twice-daily schedule, orally. Patients remained on study until disease progression or unacceptable toxicity. RESULTS: From December 1999 to May 2003, 17 patients were enrolled. Fifteen of them were male with advanced prostate cancer and two were female with advanced breast cancer. The median age of the patients was 74 years (range 56-85 years). Sixteen patients were assessable for adverse events and dose-limiting toxicity (DLT). Reason for withdrawal from the study included progressive disease (n = 12), death (n = 1) and DLT (n = 3). Two patients had evidence of grade 4 hepatic dysfunction. The MTD was not reached. There were no objective tumour responses noted. CONCLUSIONS: GLMLE appears to be a well-tolerated compound in this setting. There appears to be no objective benefit. However, grade 3/4 hepatic toxicity noted in two patients is of concern and should be considered while evaluating patients taking GLMLE or while designing studies with this agent.

Mechano-responsive room temperature luminescence variations of boron conjugated pyrene in air.

Stimuli responsive tunable luminescence is a promising field of research. Even though mechanofluorescence is widely studied, mechanophosphorescence remains unexplored. Here we report the mechano-driven fluorescence and phosphorescence variations of a pyrene tetraboronic ester derivative. The fluorochromic and room temperature phosphorescence features are supported by theoretical studies and single crystal analysis. The mechanically ground fluorescence active but phosphorescence inactive pyrene tetraboronic ester exhibits room temperature phosphorescence in air with mechanical force. The efficient intermolecular electronic coupling in the dimer formed upon scratching enables a good communication between singlet and triplet states, hence resulting in room temperature mechanophosphorescence.

The Dictyostelium LIM domain-containing protein LIM2 is essential for proper chemotaxis and morphogenesis.

We have identified limB, a gene encoding a novel LIM domain-containing protein, LIM2, in a screen for genes required for morphogenesis. limB null cells aggregate, although poorly, but they are unable to undergo morphogenesis, and the aggregates arrest at the mound stage. limB null cells exhibit an aberrant actin cytoskeleton and have numerous F-actin-enriched microspikes. The cells exhibit poor adhesion to a substratum and do not form tight cell-cell agglomerates in suspension. Furthermore, limB null cells are unable to properly polarize in chemoattractant gradients and move very poorly. Expression of limB from a prestalk-specific but not a prespore-specific promoter complements the morphogenetic defects of the limB null strain, suggesting that the limB null cell developmental defect results from an inability to properly sort prestalk cells. LIM2 protein is enriched in the cortex of wild-type cells, although it does not colocalize with the actin cytoskeleton. Our analysis indicates that LIM2 is a new regulatory protein that functions to control rearrangements of the actin cytoskeleton and is required for cell motility and chemotaxis. Our findings may be generally applicable to understanding pathways that control cell movement and morphogenesis in all multicellular organisms. Structure function studies on the LIM domains are presented.

Macroscopic technique for the evaluation of oral tongue tumour thickness: a reliable intraoperative method.

There is no reliable method to assess tumour thickness preoperatively or intraoperatively in cases of oral tongue squamous cell carcinoma (SCC). The purpose of this study was to evaluate the efficacy of a macroscopic technique to measure tumour thickness. This was a prospective study of 51 consecutive patients with T1/T2 primary SCC of the oral tongue. All patients underwent primary resection with ipsilateral neck dissection. Thickness measurements were obtained using Vernier calipers on the fresh specimen. The technique was correlated with the microscopic evaluation statistically using (1) Pearson's correlation coefficient, (2) intra-class correlation, and (3) Bland-Altman plot with 95% confidence intervals. On comparing the macroscopic technique to the microscopic evaluation, Pearson's correlation (r) was 0.915 (P<0.001). The inter-rater reliability using the intra-class correlation coefficient was 0.955. The Bland-Altman plot to test the agreement between the techniques showed the average difference between macroscopic thickness and microscopic thickness (bias) to be -0.421, with 95% limits of agreement of -3.166 and 2.82. There was a significant correlation and agreement between the macroscopic and microscopic measures of tumour thickness. The macroscopic technique could be used as a reliable tool to measure tumour thickness intraoperatively, prior to neck dissection.

Differential expression of the arabidopsis nia1 and nia2 genes. cytokinin-induced nitrate reductase activity is correlated with increased nia1 transcription and mrna levels

Nitrate reductase (NR) activity increased up to 14-fold in response to treatment of Arabidopsis thaliana seedlings with the cytokinin benzyladenine. NR induction was observed in seedlings germinated directly on cytokinin-containing medium, seedlings transferred to cytokinin medium, and seedlings grown in soil in which cytokinin was applied directly to the leaves. About the same level of induction was seen in both wild-type and Nia2-deletion mutants, indicating that increased NR activity is related to the expression of the minor NR gene, Nia1. The steady-state Nia1 mRNA level was increased severalfold in both wild-type and mutant seedlings after benzyladenine treatment. Transcript levels of the Nia2 gene, which is responsible for 90% of the NR activity in developing wild-type seedlings, did not show any changes upon cytokinin treatment. Nuclear run-on assays demonstrated that Nia1 gene transcription increased dramatically after cytokinin treatment.

Safety of newer generation anti-epileptic drugs in non-accidental overdose: an Irish population study.

UNLABELLED: Seven new anti-epileptic drugs (AEDs) have become available in Ireland over the last 10 years; data from animal models and clinical trials suggest that they have a superior safety profile to older AEDs. A specific relationship between epilepsy and psychiatric co-morbidity has long been recognised, including the relationship between epilepsy and suicide. AEDs are common agents taken in intentional drug overdoses. We undertook a study to review the frequency and outcome of non-accidental overdose with seven new AEDS in an Irish population from 1996 to 2000. METHOD: All reported cases of drug overdoses with AEDs from 1996 to 2000 were reviewed. Data was provided by the National Poisons Information Centre, Beaumont Hospital and the Central Statistics Office. Medical records from Beaumont Hospital were reviewed in specific cases of serious drug toxicities. An extensive review of published literature reviewing the safety profile of these AEDs was performed and medical literature retrieved from the databases of the pharmaceutical industry was similarly reviewed. RESULTS: Of the 164 reported cases of newer AEDs, there were no fatalities among the cases followed up. CONCLUSION: The absence of mortalities and serious consequences from deliberate self-poisoning with the newer agents is supportive evidence for the superior safety profile of the newer AEDs.