Risk factors for developing COVID-19: a population-based longitudinal study (COVIDENCE UK).

BACKGROUND: Risk factors for severe COVID-19 include older age, male sex, obesity, black or Asian ethnicity and underlying medical conditions. Whether these factors also influence susceptibility to developing COVID-19 is uncertain. METHODS: We undertook a prospective, population-based cohort study (COVIDENCE UK) from 1 May 2020 to 5 February 2021. Baseline information on potential risk factors was captured by an online questionnaire. Monthly follow-up questionnaires captured incident COVID-19. We used logistic regression models to estimate multivariable-adjusted ORs (aORs) for associations between potential risk factors and odds of COVID-19. RESULTS: We recorded 446 incident cases of COVID-19 in 15 227 participants (2.9%). Increased odds of developing COVID-19 were independently associated with Asian/Asian British versus white ethnicity (aOR 2.28, 95% CI 1.33 to 3.91), household overcrowding (aOR per additional 0.5 people/bedroom 1.26, 1.11 to 1.43), any versus no visits to/from other households in previous week (aOR 1.31, 1.06 to 1.62), number of visits to indoor public places (aOR per extra visit per week 1.05, 1.02 to 1.09), frontline occupation excluding health/social care versus no frontline occupation (aOR 1.49, 1.12 to 1.98) and raised body mass index (BMI) (aOR 1.50 (1.19 to 1.89) for BMI 25.0-30.0 kg/m2 and 1.39 (1.06 to 1.84) for BMI >30.0 kg/m2 versus BMI <25.0 kg/m2). Atopic disease was independently associated with decreased odds (aOR 0.75, 0.59 to 0.97). No independent associations were seen for age, sex, other medical conditions, diet or micronutrient supplement use. CONCLUSIONS: After rigorous adjustment for factors influencing exposure to SARS-CoV-2, Asian/Asian British ethnicity and raised BMI were associated with increased odds of developing COVID-19, while atopic disease was associated with decreased odds. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT04330599).

From Petri Dish to Patient: Bioavailability Estimation and Mechanism of Action for Antimicrobial and Immunomodulatory Natural Products.

The new era of multidrug resistance of pathogens against frontline antibiotics has compromised the immense therapeutic gains of the 'golden age,' stimulating a resurgence in antimicrobial research focused on antimicrobial and immunomodulatory components of botanical, fungal or microbial origin. While much valuable information has been amassed on the potency of crude extracts and, indeed, purified compounds there are too many reports that uncritically extrapolate observed in vitro activity to presumed ingestive and/or topical therapeutic value, particularly in the discipline of ethnopharmacology. Thus, natural product researchers would benefit from a basic pharmacokinetic and pharmacodynamic understanding. Furthermore, therapeutic success of complex mixtures or single components derived therefrom is not always proportionate to their MIC values, since immunomodulation can be the dominant mechanism of action. Researchers often fail to acknowledge this, particularly when 'null' activity is observed. In this review we introduce the most up to date theories of oral and topical bioavailability including the metabolic processes affecting xenobiotic biotransformation before and after drugs reach the site of their action in the body. We briefly examine the common methodologies employed in antimicrobial, immunomodulatory and pharmacokinetic research. Importantly, we emphasize the contribution of synergies and/or antagonisms in complex mixtures as they affect absorptive processes in the body and sometimes potentiate activity. Strictly in the context of natural product research, it is important to acknowledge the potential for chemotypic variation within important medicinal plants. Furthermore, polar head space and rotatable bonds give a priori indications of the likelihood of bioavailability of active metabolites. Considering this and other relatively simple chemical insights, we hope to provide the basis for a more rigorous scientific assessment, enabling researchers to predict the likelihood that observed in vitro anti-infective activity will translate to in vivo outcomes in a therapeutic context. We give worked examples of tentative pharmacokinetic assessment of some well-known medicinal plants.

WITHDRAWN: Gluten- and casein-free diets for autistic spectrum disorder.

BACKGROUND: It has been suggested that peptides from gluten and casein may have a role in the origins of autism and that the physiology and psychology of autism might be explained by excessive opioid activity linked to these peptides. Research has reported abnormal levels of peptides in the urine and cerebrospinal fluid of people with autism. OBJECTIVES: To determine the efficacy of gluten and/or casein free diets as an intervention to improve behaviour, cognitive and social functioning in individuals with autism. SEARCH METHODS: The following electronic databases were searched: CENTRAL(The Cochrane Library Issue 2, 2007), MEDLINE (1966 to April 2007), PsycINFO (1971 to April 2007), EMBASE (1974 to April 2007), CINAHL (1982 to April 2007), ERIC (1965 to 2007), LILACS (1982 to April 2007), and the National Research register 2007 (Issue1). Review bibliographies were also examined to identify potential trials. SELECTION CRITERIA: All randomised controlled trials (RCT) involving programmes which eliminated gluten, casein or both gluten and casein from the diets of individuals diagnosed with an autistic spectrum disorder. DATA COLLECTION AND ANALYSIS: Abstracts of studies identified in searches of electronic databases were assessed to determine inclusion by two independent authors The included trials did not share common outcome measures and therefore no meta-analysis was possible. Data are presented in narrative form. MAIN RESULTS: Two small RCTs were identified (n = 35). No meta-analysis was possible. There were only three significant treatment effects in favour of the diet intervention: overall autistic traits, mean difference (MD) = -5.60 (95% CI -9.02 to -2.18), z = 3.21, p=0.001 (Knivsberg 2002) ; social isolation, MD = -3.20 (95% CI -5.20 to 1.20), z = 3.14, p = 0.002) and overall ability to communicate and interact, MD = 1.70 (95% CI 0.50 to 2.90), z = 2.77, p = 0.006) (Knivsberg 2003). In addition three outcomes showed no significant difference between the treatment and control group and we were unable to calculate mean differences for ten outcomes because the data were skewed. No outcomes were reported for disbenefits including harms. AUTHORS' CONCLUSIONS: Research has shown of high rates of use of complementary and alternative therapies (CAM) for children with autism including gluten and/or casein exclusion diets. Current evidence for efficacy of these diets is poor. Large scale, good quality randomised controlled trials are needed.

Hypothalamic POMC or MC4R deficiency impairs counterregulatory responses to hypoglycemia in mice.

OBJECTIVE: Life-threatening hypoglycemia is a major limiting factor in the management of diabetes. While it is known that counterregulatory responses to hypoglycemia are impaired in diabetes, molecular mechanisms underlying the reduced responses remain unclear. Given the established roles of the hypothalamic proopiomelanocortin (POMC)/melanocortin 4 receptor (MC4R) circuit in regulating sympathetic nervous system (SNS) activity and the SNS in stimulating counterregulatory responses to hypoglycemia, we hypothesized that hypothalamic POMC as well as MC4R, a receptor for POMC derived melanocyte stimulating hormones, is required for normal hypoglycemia counterregulation. METHODS: To test the hypothesis, we induced hypoglycemia or glucopenia in separate cohorts of mice deficient in either POMC or MC4R in the arcuate nucleus (ARC) or the paraventricular nucleus of the hypothalamus (PVH), respectively, and measured their circulating counterregulatory hormones. In addition, we performed a hyperinsulinemic-hypoglycemic clamp study to further validate the function of MC4R in hypoglycemia counterregulation. We also measured Pomc and Mc4r mRNA levels in the ARC and PVH, respectively, in the streptozotocin-induced type 1 diabetes mouse model and non-obese diabetic (NOD) mice to delineate molecular mechanisms by which diabetes deteriorates the defense systems against hypoglycemia. Finally, we treated diabetic mice with the MC4R agonist MTII, administered stereotaxically into the PVH, to determine its potential for restoring the counterregulatory response to hypoglycemia in diabetes. RESULTS: Stimulation of epinephrine and glucagon release in response to hypoglycemia or glucopenia was diminished in both POMC- and MC4R-deficient mice, relative to their littermate controls. Similarly, the counterregulatory response was impaired in association with decreased hypothalamic Pomc and Mc4r expression in the diabetic mice, a phenotype that was not reversed by insulin treatment which normalized glycemia. In contrast, infusion of an MC4R agonist in the PVH restored the counterregulatory response in diabetic mice. CONCLUSION: In conclusion, hypothalamic Pomc as well as Mc4r, both of which are reduced in type 1 diabetic mice, are required for normal counterregulatory responses to hypoglycemia. Therefore, enhancing MC4R function may improve hypoglycemia counterregulation in diabetes.

Patient groups, clinicians and healthcare professionals agree - all test results need to be seen, understood and followed up.

Background Diagnostic testing provides integral information for the prevention, diagnosis, treatment and management of disease. Inadequate test result reporting and follow-up is a major risk to patient safety. Factors contributing to failure to follow-up test results include unclear delineation of responsibility about who is meant to act on a test result; poor coordination across different levels of care; and the absence of integrated health information systems for the efficient information communication. Methods A 2016 Australian Stakeholder Forum brought together over 30 representatives from 14 different consumer, clinical and management stakeholder organisations to discuss safe and effective test result communication, management and follow-up. Thematic analysis was conducted drawing on multimodal data collected in the form of observational fieldnotes and document artefacts produced by participants. Results The forum identified major challenges which pose immediate risks to patient safety. Participants recommended priorities for addressing issues relating to: (i) the governance of test result management processes; (ii) integration of health care processes through the utilisation of effective digital health solutions; and (iii) involving patients as key partners in the decision-making and care process. Conclusions Stakeholder groups diverged slightly in their priorities. Consumers highlighted the lack of patient involvement in the test result management process but were less concerned about standardisation of reports and critical result thresholds than pathologists. The forum foregrounded the need for a systems approach, capable of identifying and addressing interconnections and multiple factors that contribute to poor test result follow-up, with a strong emphasis on enhancing the contribution of patients.

An evaluation of risk factors to predict target concentration non-attainment in critically ill patients prior to empiric ß-lactam therapy.

To determine whether target concentration non-attainment can be anticipated in critically ill patients prior to initiating empiric ß-lactam antibiotic therapy based on readily available clinical factors. Retrospective review of consecutive patients treated with piperacillin or meropenem and who underwent therapeutic drug monitoring (TDM) at St Vincent's Hospital (Sydney, Australia) between January 2013 and December 2015 was performed. Predefined subgroups were patients who received continuous renal replacement therapy (CRRT) and those who did not (non-CRRT). Potential risk factors were evaluated by correlation with ß-lactam antibiotic trough concentrations (Cmin) lower than or equal to targeted minimum inhibitory concentration (MIC). Only the first drug concentration after initiation of the antibiotic treatment was included to reflect empirical dose selection. A total of n = 249 patients (piperacillin, n = 169; meropenem, n = 80) were investigated. For non-CRRT patients (n = 210), multivariate analysis demonstrated the following: male gender (p = 0.006); younger age (p = 0.015); prescribed daily antibiotic dose less than 1.5 times the product information recommendations (p = 0.004); lack of positive microbiology (p = 0.006); lower overall illness severity (p = 0.005); and estimated glomerular filtration rate (eGFR) ≥ 90 mL/min/1.73 m2 (p < 0.001), to be associated with Cmin ≤ MIC. No predictor variable was found to be significantly associated with Cmin ≤ MIC for the CRRT cohort. Evaluating the risk of target concentration non-attainment using simple clinical factors is possible at the bedside for non-CRRT patients prior to empiric antibiotic initiation. Clinicians should be wary of selecting doses based on the product information especially when treating younger male patients with apparently 'normal' renal function.

Novel tricyclics (e.g., GSK945237) as potent inhibitors of bacterial type IIA topoisomerases.

During the course of our research on the lead optimisation of the NBTI (Novel Bacterial Type II Topoisomerase Inhibitors) class of antibacterials, we discovered a series of tricyclic compounds that showed good Gram-positive and Gram-negative potency. Herein we will discuss the various subunits that were investigated in this series and report advanced studies on compound 1 (GSK945237) which demonstrates good PK and in vivo efficacy properties.

The Iridoid Myodesert-1-ene and Elemol/Eudesmol are found in Distinct Chemotypes of the Australian Aboriginal Medicinal Plant Eremophila dalyana (Scrophulariaceae).

The strongly aromatic Australian desert species Eremophila dalyana is an Aboriginal medicinal plant that continues to be used today in Central Australia in the treatment of respiratory complaints and Sarcoptes scabiei infestation. Using hydrodistillation of aerial parts of the plant, the new natural product myodesert-l- ene was isolated in two disjunct populations at up to 98% of the volatiles present in the hydrodistilled oils. Weak antimicrobial activities were observed for whole oils and myodesert-l-ene. Activities in the hydrodistilled oil were attributed to the antimicrobial sesquiterpenes elemol and eudesmol which showed good activity when isolated and were relatively abundant in the chemotype used medicinally. The biogenesis of myodesert-l-ene from iridodial is proposed.

Guidance concerning the use of glycated haemoglobin (HbA1c) for the diagnosis of diabetes mellitus.

Glycated haemoglobin (HbA1c) assessment for the diagnosis of diabetes mellitus overcomes many practical problems associated with traditional blood glucose measurements. However, the test is not without limitations of which the medical practitioner needs to be aware. The possibility of an individual having a medical condition that interferes with the test should always be considered, even though these conditions are rare in most Australian communities. Appropriately used, HbA1c assessment should provide a cost-effective, efficient and simple tool for the early diagnosis of type 2 diabetes.

Glycemic effects and safety of L-Glutamine supplementation with or without sitagliptin in type 2 diabetes patients-a randomized study.

BACKGROUND AND AIMS: L-glutamine is an efficacious glucagon-like peptide (GLP)-1 secretagogue in vitro. When administered with a meal, glutamine increases GLP-1 and insulin excursions and reduces postprandial glycaemia in type 2 diabetes patients. The aim of the study was to assess the efficacy and safety of daily glutamine supplementation with or without the dipeptidyl peptidase (DPP)-4 inhibitor sitagliptin in well-controlled type 2 diabetes patients. METHODS: Type 2 diabetes patients treated with metformin (n = 13, 9 men) with baseline glycated hemoglobin (HbA1c) 7.1±0.3% (54±4 mmol/mol) received glutamine (15 g bd)+ sitagliptin (100 mg/d) or glutamine (15 g bd) + placebo for 4 weeks in a randomized crossover study. RESULTS: HbA1c (P = 0.007) and fructosamine (P = 0.02) decreased modestly, without significant time-treatment interactions (both P = 0.4). Blood urea increased (P<0.001) without a significant time-treatment interaction (P = 0.8), but creatinine and estimated glomerular filtration rate (eGFR) were unchanged (P≥0.5). Red blood cells, hemoglobin, hematocrit, and albumin modestly decreased (P≤0.02), without significant time-treatment interactions (P≥0.4). Body weight and plasma electrolytes remained unchanged (P≥0.2). CONCLUSIONS: Daily oral supplementation of glutamine with or without sitagliptin for 4 weeks decreased glycaemia in well-controlled type 2 diabetes patients, but was also associated with mild plasma volume expansion. TRIAL REGISTRATION: ClincalTrials.gov NCT00673894.

Chemogeography and antimicrobial activity of essential oils from Geijera parviflora and Geijera salicifolia (Rutaceae): two traditional Australian medicinal plants.

Essential oils were hydrodistilled from 27 specimens of Geijera parviflora Lindl., (Rutaceae) and nine specimens of Geijera salicifolia Schott, collected over a wide geographic range in New South Wales, Queensland and South Australia. Essential oils were produced by traditional hydrodistillation and characterised using GC-MS. From one specimen a serendipitous discovery was made of bioactive coumarins dissolved in the hydrosol, which were the coumarins isopsoralen, xanthyletine and osthole. These coumarins were not present in the essential oil from that specimen. Using essential oil composition from all specimens, principal component analysis (PCA) demonstrated nine clusters for G. parviflora and three for G. salicifolia. Some clusters are representative of previously described chemotypes and some are reflective of possible chemotypes requiring more comprehensive sampling for confirmation. Thus, another three or four possible chemotypes of G. parviflora and one of G. salicifolia have been tentatively identified. Using micro-titre plate broth dilution assays, antibacterial and antifungal activity of all chemotypes was investigated. In this regard, the 'green oil' chemotype, restricted to G. parviflora, with major components linalool, geijerene/pregeijerene, 1,8-cineol and bicyclogermacrene, demonstrated the highest antimicrobial and free radical scavenging activity. Thus, in the light of traditional use reports of local analgaesia and bioactivity demonstrated in the current study, oils from select chemotypes of G. parviflora may be useful in suitably compounded lotions and creams designed for topical antimicrobial applications and local pain relief. In addition, because major components are known for insecticidal activities, such lotions may also be useful as topically applied insect repellents.

Isolation and characterisation of (-)-genifuranal: the principal antimicrobial component in traditional smoking applications of Eremophila longifolia (Scrophulariaceae) by Australian aboriginal peoples.

ETHNOPHARMACOLOGICAL SIGNIFICANCE: Eremophila longifolia is considered by some Australian Aboriginal tribal groups to be among the most significant of the medicinal plants in contemporary and traditional use. Usage modalities traditionally involved lipophilic extraction into animal fats and most importantly, ceremonial or medicinal smoking applications, involving the fumigation of mothers and infants following childbirth or boys following circumcision. An attempt was made to replicate the smoking modalities used by Australian Aboriginal people in the laboratory to identify bioactive compounds. MATERIALS AND METHODS: Two methods were used to produce smoke extracts; smoke was channelled through a condenser then bubbled into solvent, or bubbled directly into H2O then partitioned into chloroform followed by butanol. Extracts were used, firstly for antimicrobial screening using micro-titre plate broth dilution to produce minimum inhibitory concentrations (MIC), and secondly for chemical analysis. Structure elucidation of an abundant compound isolated from the smoke extract was performed using 2D-NMR and derivatisation. RESULTS: Significant antimicrobial activity (<1.0 mg/ml) was produced using the smoke extracts against the Gram-positive species Staphylococcus aureus, Bacillus subtilis and the yeast Candida albicans. A major component of the smoke with strong antimicrobial activity (0.13-0.5 mg/ml) was isolated which we have named (-)-genifuranal. Structure elucidation using 2D-NMR and derivatisation demonstrated genifuranal to be 5,6-dihydro-4H-cyclopenta[c]furan-4-ylacetaldehyde. Genifuranal is not observed in the leaves before heating, but is produced in the smoking or heating process and is thought to derive from hydrolysis and rearrangement of geniposidic acid or a related glycoside. Only geographically specific specimens of Eremophila longifolia produced (-)-genifuranal, which strongly supports previous hypothesised geographical variation in traditional usage, reflective of phytochemical variation. CONCLUSION: It would appear that genifuranal is the medicinal principal involved in traditional use of Eremophila longifolia when smoking modalities are used. Topical treatments traditionally produced by lipophilic extraction into animal fats are not likely to have had genifuranal present, as the mechanism for its formation requires heat.

Medicinal compounds, chemically and biologically characterised from extracts of Australian Callitris endlicheri and C.glaucophylla (Cupressaceae): used traditionally in Aboriginal and colonial pharmacopoeia.

ETHNOPHARMACOLOGICAL SIGNIFICANCE: Callitrisendlicheri and C.glaucophylla were highly valued by Australian Aboriginal people for use in medicinal applications. Pine needles were prepared using modalities of either smoking or topical preparations, requiring either aqueous or lipophilic extraction into animal fat. Extracts treated various ailments consistent with pathogenic infection, or other topical or tracheal ailments not clearly elucidated in ethnopharmacological records. AIM OF THE STUDY: Here we aim firstly to investigate antimicrobial activities of both smoke, essential oil and solvent extracts and secondly to chemically characterise significant volatile compounds potentially related to medicinal or antimicrobial activities. MATERIALS AND METHODS: Essential oils were produced using traditional hydrodistillation of pine needles collected from Callitrisendlicheri and C.glaucophylla. From the same material, solvent extracts were produced separately, using acetone and methanol, and then smoke extracts were produced with separate methods described herein, using fresh needles. All extracts were screened for antimicrobial activity against a range of bacterial organisms and sporicidal activity against pathogenic fungi (Trichophytonmentagrophytes, T.interdigitalis and T.rubrum). RESULTS: Essential oils produced only modest antibacterial activity and the Callitris endlicheri essential oil had moderate antifungal activity. Smoke extracts demonstrated considerable broad spectrum antimicrobial activity, but solvent extracts demonstrated more selective activity against Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis and the yeast Candida albicans. Chemical character of essential oils was consistent with previous studies; however, solvent and smoke extracts from fresh needles produced high concentrations of potentially medicinal abietane diterpenes, specifically pisiferal, pisiferol and ferruginol; well known from Japanese species with demonstrated bioactivity. CONCLUSION: The occurrence of these diterpenes and other phenolics, in conjunction with significant antimicrobial activities from the various extracts, is in alignment with the use of Australian Callitris species in Aboriginal medicinal practice.

Composition and antimicrobial activity of the essential oils from the Phebalium squamulosum species complex (Rutaceae) in New South Wales, Australia.

Essential oils have been hydrodistilled and characterized from 21 populations of taxa currently assigned to the endemic Australian species Phebalium squamulosum (Rutaceae: Boronieae) using GC-MS, NMR and quantified using GC-FID. Essential oils were further examined using principle component analysis to distinguish chemotypes, then screened for antimicrobial activity using broth dilution and TLC-bioautography. Collections of subspecies of P. squamulosum, namely subsp. coriaceum, subsp. gracile, subsp. lineare, subsp. squamulosum, subsp. ozothamnoides and subsp. verrucosum, were made from the wild and one from a cultivated plant of known provenance within New South Wales. Results demonstrated considerable intra- and interspecific essential oil component variation, suggesting the existence of distinct chemotypes and supporting previously observed segregate species based on morphological evidence. Antimicrobial testing revealed moderate to high activity for all essential oils dominated by sesquiterpene alcohols; elemol and eudesmol isomers. Conversely, very low antimicrobial activity was observed from essential oils dominated by monoterpenes. This study constitutes the most exhaustive investigation of essential oils from P. squamulosum subspecies to date and provides the first report of antimicrobial activity.

Discovery of thiazolobenzoxepin PI3-kinase inhibitors that spare the PI3-kinase ß isoform.

A series of suitable five-membered heterocyclic alternatives to thiophenes within a thienobenzoxepin class of PI3-kinase (PI3K) inhibitors was discovered. Specific thiazolobenzoxepin 8-substitution was identified that increased selectivity over PI3Kß. PI3Kß-sparing compound 27 (PI3Kß Ki,app/PI3Kα Ki,app=57) demonstrated dose-dependent knockdown of pAKT, pPRAS40 and pS6RP in vivo as well as differential effects in an in vitro proliferation cell line screen compared to pan PI3K inhibitor GDC-0941. A new structure-based hypothesis for reducing inhibition of the PI3K ß isoform while maintaining activity against α, δ and γ isoforms is presented.

Chemical and biological characterisation of solvent extracts and essential oils from leaves and fruit of two Australian species of Pittosporum (Pittosporaceae) used in aboriginal medicinal practice.

ETHNOPHARMACOLOGICAL SIGNIFICANCE: Although no known medicinal use for Pittosporum undulatum Vent. (Pittosporaceae) has been recorded, anecdotal evidence suggests that Australian Aboriginal people used Pittosporum angustifolium Lodd., G. Lodd. & W. Lodd. topically for eczema, pruritis or to induce lactation in mothers following child-birth and internally for coughs, colds or cramps. AIMS OF THE STUDY: Essential oil composition and bioactivity as well as differential solvent extract antimicrobial activity from Pittosporum angustifolium are investigated here first, to partially describe the composition of volatiles released in traditional applications of Pittosporum angustifolium for colds or as a lactagogue, and second to investigate antibacterial activity related to topical applications. Essential oils were also investigated from Pittosporum undulatum Vent., first to enhance essential oil data produced in previous studies, and second as a comparison to Pittosporum angustifolium. MATERIALS AND METHODS: Essential oils were hydrodistilled from fruit and leaves of both species using a modified approach to lessen the negative (frothing) effect of saponins. This was achieved by floating pumice or pearlite obsidian over the mixture to crush the suds formed while boiling. Essential oil extracts were analysed using GC-MS, quantified using GC-FID then screened for antimicrobial activity using a micro-titre plate broth dilution assay (MIC). Using dichloromethane, methanol, hexane and H(2)O as solvents, extracts were produced from leaves and fruit of Pittosporum angustifolium and screened for antimicrobial activity and qualitative phytochemical character. RESULTS: Although the essential oil from leaves and fruit of Pittosporum undulatum demonstrated some component variation, the essential oil from fruits of Pittosporum angustifolium had major constituents that strongly varied according to the geographical location of collection, suggesting the existence of at least two chemotypes; one with high abundance of acetic acid decyl ester. This chemotype had high antimicrobial activity whilst the other chemotype had only moderate antimicrobial activity against the three microbial species investigated here. This result may support the occurrence of geographical specificity with regard to ethnopharmacological use. Antimicrobial activity screening of the solvent extracts from Pittosporum angustifolium revealed the leaves to be superior to fruit, with water being the most suitable extraction solvent. CONCLUSION: To the best of our knowledge, this study constitutes the first time essential oils, and solvent extracts from the fruits of Pittosporum angustifolium, have been examined employing comprehensive chemical and biological analysis. The essential oil composition presented in this paper, includes components with structural similarity as chemosemiotic compounds involved in mother-infant identification, which may have significance with regard to traditional applications as a lactagogue.

Chemical and biological characterization of novel essential oils from Eremophila bignoniiflora (F. Muell) (Myoporaceae): a traditional Aboriginal Australian bush medicine.

Essential oils were extracted by hydrodistillation from the traditional Australian medicinal plant Eremophila bignoniiflora, characterized chemically and then screened for bioactivity. Characterization and quantification were completed using gas chromatography-mass spectrometry (GC-MS) and GC-flame ionization detection, respectively. Antimicrobial capacity was assessed using disc diffusion and micro-titre plate broth dilution and further characterized using thin layer chromatography followed by bioautography to assign activity to separated individual active components. Antifungal capacity was investigated using micro-titre plate broth dilution against pathogenic Trichophyton species. Free radical scavenging ability was assessed using the diphenylpicrylhydradyl reaction in methanol. The predominant components of the essential oil were fenchyl-acetate and bornyl-acetate. However, bioautography indicated antimicrobial ability to be largely linked to the less abundant, more polar constituents. Oils displayed only modest antifungal ability against pathogenic Trichophyton species associated with dermatophytosis, but moderate to high antimicrobial activity, particularly against the yeast Candida albicans and the bacteria Staphylococcus epidermidis. Essential oils exhibited relatively low free radical scavenging ability. Speculation over the role of essential oils in the traditional medicinal applications of E. bignoniiflora follows, exploring correlations between traditional use and investigated bioactivities.

Activation of dopamine neurons is critical for aversive conditioning and prevention of generalized anxiety.

Generalized anxiety is thought to result, in part, from impairments in contingency awareness during conditioning to cues that predict aversive or fearful outcomes. Dopamine neurons of the ventral midbrain exhibit heterogeneous responses to aversive stimuli that are thought to provide a critical modulatory signal to facilitate orientation to environmental changes and assignment of motivational value to unexpected events. Here we describe a mouse model in which activation of dopamine neurons in response to an aversive stimulus is attenuated by conditional genetic inactivation of functional NMDA receptors on dopamine neurons. We discovered that altering the magnitude of excitatory responses by dopamine neurons in response to an aversive stimulus was associated with impaired conditioning to a cue that predicts an aversive outcome. Impaired conditioning by these mice was associated with the development of a persistent, generalized anxiety-like phenotype. These data are consistent with a role for dopamine in facilitating contingency awareness that is critical for the prevention of generalized anxiety.

Identification of antibacterial constituents from the indigenous Australian medicinal plant Eremophila duttonii F. Muell. (Myoporaceae).

This paper reports on the isolation and identification of antibacterial constituents from the indigenous Australian medicinal plant Eremophila duttonii F. Muell. (Myoporaceae). Preparations derived from this plant are used by indigenous populations in the topical treatment of minor wounds, otitis and ocular complaints, and as a gargle for sore throat. Several authors have reported extracts of this plant to effect rapid bacteriolysis and inhibit growth of a wide range of Gram-positive micro-organisms. In other studies involving screening of native medicinal plants for antibacterial activity, extracts of Eremophila duttonii have been reported to consistently exhibit the highest potency amongst all species included. From a hexane extract, we identified two diterpenes of the serrulatane class, the principal constituents responsible for antibacterial activity and present as major constituents of the resinous leaf cuticle: serrulat-14-en-7,8,20-triol (1) and serrulat-14-en-3,7,8,20-tetraol (2). In addition, a hydroxylated furanosesquiterpene with mild antibacterial activity which appeared to be a novel compound was isolated from the extract and tentatively identified as 4-hydroxy-4-methyl-1-(2,3,4,5-tetrahydro-5-methyl[2,3'-bifuran]-5-yl) pentan-2-one. Minimum inhibitory concentrations for each of the compounds against three Gram-positive bacteria: Staphylococcus aureus (ATCC 29213), Staphylococcus epidermidis (ATCC 12228) and Streptococcus pneumoniae (ARL 10582), were determined using a micro-titre plate broth dilution assay.