Vismodegib in the treatment of advanced BCC.

Basal-cell carcinoma (BCC) is the most commonly diagnosed malignancy, comprising over 80 per thousand of non-melanoma skin cancers. Surgical excision is adequate treatment for most BCC's. Options are however limited for the minority of patients presenting with locally advanced inoperable or metastatic BCC. The Hedgehog signalling pathway is a critical driver in the pathogenesis of both sporadic and hereditary BCC. On 31st January 2012, based on a phase II clinical trial the US Food and Drug Administration approved Vismodegib (Erivedge, Roche) a first-in-class, small-molecule oral Hedgehog-inhibitor for the treatment of locally advanced inoperable and metastatic BCC. We present our experience treating the first Irish patient with this agent.

Phylogenetic delineation of the novel phylum Armatimonadetes (former candidate division OP10) and definition of two novel candidate divisions.

Small-subunit (SSU) rRNA gene sequences associated with the phylum Armatimonadetes were analyzed using multiple phylogenetic methods, clarifying both the phylum boundary and the affiliation of previously ambiguous groupings. Here we define the Armatimonadetes as 10 class-level groups and reclassify two previously associated groups as candidate divisions WS1 and FBP.

Evaluation of lactic acid bacterium from chilli waste as a potential antifungal agent for wood products.

AIMS: The aim of this study was to isolate lactic acid bacteria from chilli waste and evaluate metabolites produced for the ability to arrest wood decay. METHODS AND RESULTS: Using an optical density screening method, one bacterium (isolate C11) was identified as having pronounced antifungal properties against Oligoporus placenta. This isolate was identified as Lactobacillus brevis by 16S rRNA gene sequencing. To determine antifungal activity in wood, Pinus radiata blocks were impregnated with Lact. brevis [C11] cell-free supernatant and exposed to brown rot fungi O. placenta, Antrodia xantha and Coniophora puteana. The treated timber demonstrated resistance to degradation from all fungi. The antifungal metabolites were heat stable and not affected by proteinase K, but were affected by neutralization with NaOH suggesting the metabolites were of an acidic nature. The presence of lactic and acetic acid was confirmed by HPLC analysis. CONCLUSIONS: Lactobacillus brevis [C11] produced acidic metabolites that were able to inhibit the growth of wood decay fungi and subsequent wood decay. SIGNIFICANCE AND IMPACT OF THE STUDY: Traditional wood treatments are becoming an environmental issue as the public demands more benign options. The use of lactic acid bacteria which are considered safe for general use is a potential alternative to the conventional heavy metal chemicals currently in use.

Discovery of a 25-cm asteroid clast in the giant Morokweng impact crater, South Africa.

Meteorites provide a sample of Solar System bodies and so constrain the types of objects that have collided with Earth over time. Meteorites analysed to date, however, are unlikely to be representative of the entire population and it is also possible that changes in their nature have occurred with time. Large objects are widely believed to be completely melted or vaporized during high-angle impact with the Earth. Consequently, identification of large impactors relies on indirect chemical tracers, notably the platinum-group elements. Here we report the discovery of a large (25-cm), unaltered, fossil meteorite, and several smaller fragments within the impact melt of the giant (> 70 km diameter), 145-Myr-old Morokweng crater, South Africa. The large fragment (clast) resembles an LL6 chondrite breccia, but contains anomalously iron-rich silicates, Fe-Ni sulphides, and no troilite or metal. It has chondritic chromium isotope ratios and identical platinum-group element ratios to the bulk impact melt. These features allow the unambiguous characterization of an impactor at a large crater. Furthermore, the unusual composition of the meteorite suggests that the Morokweng asteroid incorporated part of the LL chondrite parent body not represented by objects at present reaching the Earth.

Complete skin examination is essential in the assessment of dermatology patients: findings from 483 patients.

BACKGROUND: Dermatological teaching has traditionally stressed that complete skin examination is essential in the assessment of patients with potential skin disease. OBJECTIVES: To determine whether complete skin examination results in increased diagnoses of skin malignancies that would not have been discovered otherwise. METHODS: New patients (n = 483) attending a dermatology clinic in a university teaching hospital and private dermatology practice had a complete skin examination, as is our normal practice. These patients were seen over a 9-month period (January-September 2009). All patients were examined by the same consultant dermatologist. Data were collected on patients' sex, age, presenting complaint and findings on complete skin examination. RESULTS: Two nodular malignant melanomas with mean Breslow thickness of 0·6 mm (0·4%) and one melanoma in situ were identified at sites distant from the patient's presenting complaint. Sixteen patients (3·3%) had a basal cell carcinoma that would not have been discovered if the presenting lesion alone had been examined. Thirty-three patients (6·8%) had actinic keratoses or squamous cell carcinoma in situ and nine (1·9%) had dysplastic naevi. A further 21 patients (4·3%) had a suspicious lesion biopsied or excised with subsequent benign histology. Seventy-three patients (15·1%) had other benign dermatological diagnoses requiring treatment or investigation. CONCLUSIONS: In a 9-month period, in a sample of 483 new patients, three patients (0·6%) had potentially lethal skin malignancies identified that would not have been diagnosed without a complete skin examination. Sixteen (3·3%) patients had basal cell carcinomas that would have been missed without complete skin examination. This study confirms the traditional teaching that complete skin examination has the potential to reduce morbidity and mortality from cutaneous malignancy.

(Sub)stellar companions shape the winds of evolved stars.

Binary interactions dominate the evolution of massive stars, but their role is less clear for low- and intermediate-mass stars. The evolution of a spherical wind from an asymptotic giant branch (AGB) star into a nonspherical planetary nebula (PN) could be due to binary interactions. We observed a sample of AGB stars with the Atacama Large Millimeter/submillimeter Array (ALMA) and found that their winds exhibit distinct nonspherical geometries with morphological similarities to planetary nebulae (PNe). We infer that the same physics shapes both AGB winds and PNe; additionally, the morphology and AGB mass-loss rate are correlated. These characteristics can be explained by binary interaction. We propose an evolutionary scenario for AGB morphologies that is consistent with observed phenomena in AGB stars and PNe.

A male-producing strain of the house fly.

An autosome inherited by male offspring only and a temperature-sensitive lethal factor have been combined in a house fly strain which produces both male and female progeny when reared at 25.6 degrees C but only male progeny when reared at 33.3 degrees C.

Communicating biosecurity information to Australian-registered veterinarians.

OBJECTIVE: Updating veterinarians (vets) on the latest biosecurity resources, information and alerts is important to ensure protection of domesticated and native animals. This preliminary questionnaire aimed to better understand the communication preferences of Australian-registered vets for biosecurity information, and their trust of these sources. METHODS: An online questionnaire asking vets about their current communication preferences for biosecurity information, and their level of trust of these was created and distributed to Australian-registered vets. RESULTS: Survey respondents (158) use and highly trust communication from (in order) vet and animal health organisations, vet surgeons' boards, the scientific literature, and government agencies. CONCLUSIONS: This preliminary study identifies that using vet surgeon's boards, government agencies and vet and animal health organisations may be an effective means for communicating biosecurity information to vets. Future research should consider which sources vets trust and why, to facilitate effective communication to them and the clients they serve.

Exchange Bias in Bulk α - Fe / γ - Fe 70 Mn 30 Nanocomposites for Permanent Magnet Applications.

Here we report on the microstructural factors influencing the formation of the interfacial exchange bias effect in three-dimensional transition-metal-based nanocomposite systems, with relevance to permanent magnet applications. Bulk phase-separated nanocomposites consisting of the ferromagnetic α -Fe and metastable antiferromagnetic γ - Fe 70 Mn 30 phases exhibit a notable low-temperature exchange bias and substantial coercivity ( H ex = 24.6 kA / m , H C = 95.7 kA / m ) as well as a near room-temperature blocking temperature. Structural investigation by synchrotron X-ray diffraction, neutron scattering, and transmission electron microscopy confirm that the ferromagnetic α -Fe phase nucleates as small precipitates ( d ≈ 50 nm ) at the grain boundaries of the antiferromagnetic γ - Fe 70 Mn 30 grains ( d = 360 - 740 nm ) and grows anisotropically upon heat treatment, resulting in an elliptical geometry. These results indicate that optimization of the exchange bias effect in bulk nanocomposite systems may be achieved through maximizing the surface-to-volume ratio of ferromagnetic precipitates in an antiferromagnetic matrix, enhancing the magnetocrystalline anisotropy of the antiferromagnetic phase to facilitate interfacial pinning and ensuring a balanced distribution of the ferromagnetic and antiferromagnetic phases. This work further clarifies critical factors influencing the formation of an exchange bias in an inexpensive transition-metal-based bulk nanocomposite system with potential for scalable production.

Prior exposure to non-pathogenic calicivirus RCV-A1 reduces both infection rate and mortality from rabbit haemorrhagic disease in a population of wild rabbits in Australia.

Mortality caused by rabbit haemorrhagic disease virus (RHDV) in wild rabbits is reduced in parts of Australia where the related, non-pathogenic calicivirus RCV-A1 is endemic. Laboratory experiments previously showed that prior infection with RCV-A1 enabled rabbits to better withstand subsequent infection with highly virulent RHDV, and this was assumed to explain higher survival. Here, we analyse serological data from the field suggesting that reduced mortality rates among wild rabbits may also result from rabbits previously infected with RCV-A1 having a reduced likelihood of RHDV infection. We discuss the possible mechanisms underlying this finding and its implications. The methods we describe for analysing field data gave far greater insights into epidemiological processes and virus interactions than gained from reporting basic seroprevalence rates alone.

The effects of posture and isoproterenol on the velocity of left ventricular contraction in man. The reciprocal relationship between left ventricular volume and myocardial wall force during ejection on mean rate of circumferential shortening.

A study was performed in five normal men in whom left ventricular volume was measured by thermodilution in the supine and 60 degrees head-up postures, in the control state, and then during steady-state response to isoproterenol. The mean rate of circumferential shortening of the left ventricle was calculated for each of the postures in both inotropic states and was found to remain constant in the control state at 12.5 +/-0.6 cm/sec in the supine posture and 13.3 +/-0.5 cm/sec in the tilted posture. Similarly, mean rate of circumferential shortening remained constant in response to the positive inotropic effect of isoproterenol at 20.9 +/-0.5 cm/sec in the supine position and 20.7 +/-0.5 cm/sec in the tilted posture. It is concluded that the constancy of mean rate of circumferential shortening over the relatively broad physiologic range of left ventricular end-diastolic volume and mean force of ejection during a given state of myocardial contractility represents the coupled reciprocal influences of ventricular wall tension and myocardial fiber length on the velocity of ventricular wall shortening. Unlike stroke work, stroke power, and mean rate of left ventricular ejection, which are volume-dependent parameters of myocardial performance, the mean rate of circumferential shortening appears to be a reasonable index of left ventricular contractility, which in steady-state conditions is independent of left ventricular end-diastolic volume and mean ventricular wall force of ejection. In this study, changes in mean rate of circumferential shortening associated with changes of heart rate were small and variable.

'Venus trapped, Mars transits': Cu and Fe redox chemistry, cellular topography and in situ ligand binding in terrestrial isopod hepatopancreas.

Woodlice efficiently sequester copper (Cu) in 'cuprosomes' within hepatopancreatic 'S' cells. Binuclear 'B' cells in the hepatopancreas form iron (Fe) deposits; these cells apparently undergo an apocrine secretory diurnal cycle linked to nocturnal feeding. Synchrotron-based µ-focus X-ray spectroscopy undertaken on thin sections was used to characterize the ligands binding Cu and Fe in S and B cells of Oniscus asellus (Isopoda). Main findings were: (i) morphometry confirmed a diurnal B-cell apocrine cycle; (ii) X-ray fluorescence (XRF) mapping indicated that Cu was co-distributed with sulfur (mainly in S cells), and Fe was co-distributed with phosphate (mainly in B cells); (iii) XRF mapping revealed an intimate morphological relationship between the basal regions of adjacent S and B cells; (iv) molecular modelling and Fourier transform analyses indicated that Cu in the reduced Cu(+) state is mainly coordinated to thiol-rich ligands (Cu-S bond length 2.3 Å) in both cell types, while Fe in the oxidized Fe(3+) state is predominantly oxygen coordinated (estimated Fe-O bond length of approx. 2 Å), with an outer shell of Fe scatterers at approximately 3.05 Å; and (v) no significant differences occur in Cu or Fe speciation at key nodes in the apocrine cycle. Findings imply that S and B cells form integrated unit-pairs; a functional role for secretions from these cellular units in the digestion of recalcitrant dietary components is hypothesized.

Regulation of expression of methane monooxygenases by copper ions.

Many methanotrophs contain both a soluble and a particulate methane monooxygenase. A unique metabolic switch, mediated by copper ions, regulates the expression of these enzymes. When the copper-to-biomass ratio of the cell is low, the soluble enzyme is expressed, and when the copper-to-biomass ratio is high, the particulate enzyme is expressed. A model for the mechanism of this switch is proposed.

Quantification of mitral regurgitation by integrated Doppler backscatter power.

OBJECTIVES: We attempted to determine whether continuous wave Doppler backscatter power could be used to quantify mitral regurgitation. BACKGROUND: The power of a Doppler backscatter signal is proportional to the number of scatterers insonated and, hence, to the moving volume of blood. The relative power of the continuous wave Doppler signals from mitral inflow and aortic outflow is therefore proportional to the relative volumes of blood in motion. METHODS: Computer postprocessing was used to derive the relative power of the Doppler backscatter signal from the intensity of the pixels within the spectral display of anterograde aortic and mitral flow. The power ratio was used to calculate the regurgitant fraction in 20 patients (mean age 61.4 years) with mitral regurgitation. This Doppler regurgitant fraction was compared with that derived from angiographic left ventricular volume and thermodilution cardiac output. In addition, 12 normal control subjects were studied by the Doppler method. RESULTS: Mean (+/- SD) catheterization regurgitant fraction was 0.50 +/- 0.26, and mean Doppler regurgitant fraction was 0.47 +/- 0.25 (r = 0.89). The limits of agreement between the two methods by Bland-Altman analysis were -0.21 + 0.27. In normal control subjects with an expected regurgitant fraction of close to zero, mean Doppler regurgitant fraction was 0.03 +/- 0.05. CONCLUSIONS: Doppler backscatter power from mitral and aortic inflow provides a new and accurate method for quantifying mitral regurgitation.

Satisfying hydrogen bonding potential in proteins.

We have analysed the frequency with which potential hydrogen bond donors and acceptors are satisfied in protein molecules. There are a small percentage of nitrogen or oxygen atoms that do not form hydrogen bonds with either solvent or protein atoms, when standard criteria are used. For high resolution structures 9.5% and 5.1% of buried main-chain nitrogen and oxygen atoms, respectively, fail to hydrogen bond under our standard criteria, representing 5.8% and 2.1% of all main-chain nitrogen and oxygen atoms. We find that as the resolution of the data improves, the percentages fall. If the hydrogen bond criteria are relaxed many of these unsatisfied atoms form weak hydrogen bonds. However, there remain some buried atoms (1.3% NH and 1.8% CO) that fail to hydrogen bond without any immediately obvious compensating interactions.

Amino/aromatic interactions in proteins: is the evidence stacked against hydrogen bonding?

We investigate the suggestion that aromatic rings can act as hydrogen-bond acceptors in proteins, by an analysis of 55 non-homologous high-resolution protein chain structures. Approximately 10% of interactions between sp2 hybridized nitrogen atoms, from either side-chains or main-chains, and phenylalanine or tyrosine rings have the nitrogen atom positioned above the ring. In these instances, however, the sp2 nitrogen atoms tend to form stacked interactions with the aromatic rings, these geometries outnumbering amino/aromatic hydrogen bonds by around 2.5:1. The statistically expected distribution, in contrast, would have only a few stacked structures and many more with larger interplanar angles, corresponding to amino/aromatic hydrogen bonds. Thus, although we do find some of these unconventional hydrogen bonds, they are clearly disfavoured relative to stacked geometries. In stacked geometries, the nitrogen-bearing groups are observed to fulfil their hydrogen-bonding potential by forming conventional, energetically stronger, hydrogen bonds with other groups in protein or solvent. This may explain the favourability of stacking. Thus, although ab initio calculations of the gas phase interaction energies for three model systems generally favour the amino/aromatic hydrogen-bonded over the stacked geometries, the differences are small enough to be outweighed easily by the additional conventional hydrogen bonding in stacked structures.

A protective role for nitric oxide in the oxidative modification of low density lipoproteins by mouse macrophages.

Low density lipoproteins (LDL) oxidatively modified by macrophages have been shown to be atherogenic in ex vivo studies. We studied the potential role of nitric oxide (NO), a free radical produced by macrophages, in LDL modification. Human LDL (1 mg/ml) were incubated with mouse peritoneal macrophages in Ham's F-10 medium. The cells were then stimulated by interferon-gamma and tumor necrosis factor-alpha to increase their production of NO from 1.3 to 12.2 microM in 24 h, as measured by nitrite. Lipid peroxidation of LDL, as measured by thiobarbituric acid-reactive materials (TBARS), was reduced in stimulated cells in a time-dependent manner. At 24 h, the decrease was about 27%. In the presence of an NO synthase inhibitor (NG-aminophomoarginine), the generation of NO was diminished and the protection against LDL lipid peroxidation was reversed. The extent of LDL protein modification was also assessed by examining its electrophoretic mobility. It was found that macrophage NO reduced the change in LDL electromobility. These data indicate that the production of NO may inhibit the oxidative modification of LDL with cytokine-stimulated macrophages. We suggest that NO plays a protective role in limiting macrophage-induced LDL modification.

Movement phosphenes in optic neuritis: a new clinical sign.

Positive visual phenomena (phosphenes) elicited by eye movements have been described in normal individuals and in myopes with vitreous opacities. In the present paper we describe eye movement-induced phosphenes that appear to be related to optic nerve involvement in patients with optic neuritis and multiple sclerosis. This phenomenon is not associated with vitreous or retinal defects, nor is it similar to phosphenes observed in normal individuals. Instead, it shares many characteristics with the well-known Lhermitte sign and is believed to represent a similar phenomenon.