High power generation of THz from 1550-nm photoconductive emitters.

Two photoconductive emitters - one with a self-complementary square spiral antenna, and the other with a resonant slot antenna - were fabricated on a GaAs epilayer embedded with ErAs quantum dots. Driven with 1550 nm mode-locked lasers, ~117 µW broadband THz power was generated from the device with the spiral antenna, and ~1.2 µW from the device with resonant slot antenna. The optical-to-THz conversion is through extrinsic photoconductivity.

Development of multi-disciplinary breast cancer care in Southern Malawi.

The Edinburgh Malawi Breast Cancer Project, a collaborative partnership project between the Queen Elizabeth Central Hospital (QECH) Oncology Unit, Blantyre, Malawi and the Edinburgh Cancer Centre, UK, was established in 2015. The principal objective of the project is to help to develop high quality multi-disciplinary breast cancer care in Malawi. A needs assessment identified three priority areas for further improvement of breast cancer services: multi-disciplinary working, development of oestrogen receptor (ER) testing and management of clinical data. A 3-year project plan was implemented which has been conducted through a series of reciprocal training visits. Key achievements to date have been: (1) Development of a new specialist breast care nursing role; (2) Development of multi-disciplinary meetings; (3) Completion of a programme of oncology nursing education; (4) Development of a clinical database that enables prospective collection of data of all new patients with breast cancer; (5) Training of local staff in molecular and conventional approaches to ER testing. The Edinburgh Malawi Breast Cancer Project is supporting nursing education, data use and cross-specialty collaboration that we are confident will improve cancer care in Malawi. Future work will include the development of a breast cancer diagnostic clinic and a breast cancer registry.

Differential expression of microRNAs during melanoma progression: miR-200c, miR-205 and miR-211 are downregulated in melanoma and act as tumour suppressors.

BACKGROUND: The incidence of malignant melanoma is increasing faster than that for any other cancer. Histological examination of skin excision biopsies remains the standard method for melanoma diagnosis and prognosis. Significant morphological overlap between benign and malignant lesions complicates diagnosis, and tumour thickness is not always an accurate predictor of prognosis. METHODS: To identify improved molecular markers to support histological examination, we used microarray analysis of formalin-fixed and paraffin-embedded samples from different stages of melanomagenesis to identify differentially expressed microRNAs (miRNAs). Differential expression was validated by qRT-PCR, and functional studies were carried out after transfection of miRNA precursors or inhibitors into melanoma cells to modulate miRNA expression. RESULTS: In all, 20 miRNAs showed highly significant differential expression between benign naevi and either primary or metastatic melanomas, the majority being downregulated in melanoma, whereas only 2 miRNAs, namely miR-203 and miR-205, were differentially expressed between primary and metastatic melanomas. In functional in vitro assays, overexpression of miR-200c and miR-205 inhibited anchorage-independent colony formation and overexpression of miR-211 inhibited both anchorage-independent colony formation and invasion. CONCLUSION: We have identified a series of differentially expressed miRNAs that could be useful as diagnostic or prognostic markers for melanoma and have shown that three miRNAs (namely miR-200c, miR-205 and miR-211) act as tumour suppressors.

Toward a 1550 nm InGaAs photoconductive switch for terahertz generation.

We report a terahertz (THz) photoconductive switch made from a composite of metal ErAs nanoparticles embedded in In(0.53)Ga(0.47)As and coupled to a square spiral antenna. The THz output power was measured in a 77 K cryostat by using a standard hyperhemisphere-lens package, a Golay cell outside the cryostat, and a quasi-optical filter bank for spot frequency spectral measurements. Results indicate an average output power of approximately 12 microW at 22 V bias using 140 mW of optical pump power from a subpicosecond fiber mode-locked laser. In addition, the THz spectra displayed invariance to bias voltage despite operating near impact ionization.

Reflective terahertz imaging of porcine skin burns.

A reflective pulsed terahertz imaging system based on direct detection was developed and used to obtain high-resolution images of a porcine skin specimen with superficial partial-thickness (second-degree) burns. Images were also obtained of the sample through ten layers of dry medical (cotton) gauze with minimal image degradation. The burned and unburned regions of skin had large differences in terahertz reflectivity, displaying clear delineation [20 dB signal-to-noise ratio (SNR) difference signal] between both regions in the images. The terahertz images also exhibited a "halo" surrounding the burn areas that may correlate to the extent of burn injury. The system operated at a center frequency of 500 GHz with 125 GHz of 3 dB bandwidth and used whiskbroom scanning to generate images with a spatial resolution of 1.5 mm. Each pixel was acquired with a 16 ms integration time, resulting in a 40 dB postdetection SNR. The simplicity and high SNR of the reflective terahertz system are promising steps toward real-time terahertz medical imaging.

A clinical study assessing the tolerability and biological effects of infliximab, a TNF-alpha inhibitor, in patients with advanced cancer.

BACKGROUND: Tumour necrosis factor-alpha (TNF-alpha) is an important regulator of the chronic inflammation contributing to tumour progression. Infliximab, an anti-TNF-alpha monoclonal antibody was investigated in this trial of patients with advanced cancer. The primary objectives were to determine the safety profile and biological response of infliximab in a cancer population. Clinical response was a secondary objective. PATIENTS AND METHODS: Forty-one patients received infliximab at 5 mg/kg (n = 21) or 10 mg/kg (n = 20) i.v. at 0 and 2 weeks and then every 4 weeks. Post-treatment samples were measured for changes in plasma and serum TNF-alpha, CCL2, IL-6 and C-reactive protein (CRP). RESULTS: Infliximab was well tolerated with no dose-limiting toxic effects. At both doses of infliximab, neutralisation of serum TNF-alpha was observed after 1 h while plasma CCL2, IL-6 and serum CRP were decreased 24 and 48 h following infliximab administration. Seven patients experienced disease stablisation (range 10-50+ weeks). There was no evidence of disease acceleration in any patient. CONCLUSIONS: Infliximab treatment was safe and well tolerated in patients with advanced cancer. There was evidence of biological activity with baseline TNF-alpha and CCL2 being correlated with infliximab response.

Modulation of an AMPA-like glutamate receptor (SqGluR) gating by L- and D-aspartic acids.

L- and D-aspartic acids (L-Asp and D-Asp) are present in the majority of nervous systems. In phylogeny, significant levels have been reported in mollusc brains, particularly cephalopods. To examine the role of L- and D-Asp on a cephalopod receptor, we studied ligand gating of a squid glutamate receptor (SqGluR) expressed in HEK 239 (human embryonic kidney) cells. Under voltage clamp, application of L-glutamate (L-Glu; 1-30 mM), but not D-glutamate (D-Glu), or L- or D-Asp, evoked an inward current of 0.1 nA. L- or D-Asp (200 microM) applied with 20 mM L-Glu, slowed the time course of activation and inactivation of the L-Glu gated current (time constant increased from 1 s (L-Glu alone) to 3 s (D-Asp and L-Glu) and to 19 s (L-Asp and L-Glu)). Our results suggest that in molluscan systems, aspartic acid could act as a neuromodulator during glutamatergic transmission and could significantly alter synaptic integration by slowing glutamate receptor gating.

Resonant-optical-cavity photoconductive switch with 0.5% conversion efficiency and 1.0 W peak power.

We report a new photoconductive switch having an average output power of 44 microW, an instantaneous bandwidth of approximately 300 GHz, an output pulse width of approximately 2.2 ps, a peak output power of approximately 1.0 W, and an optical-to-electrical conversion efficiency of approximately 0.5% when pumped by a palm-sized mode-locked free-space laser at lambda=780.6 nm with an average power of 8.7 mW and an optical pulse width of approximately -230 fs. The switch is made from an ErAs:GaAs epitaxial layer inside a resonant optical cavity and coupled to a planar three-turn square spiral antenna.

Tumorigenicity assessments of Per.C6 cells and of an Ad5-vectored HIV-1 vaccine produced on this continuous cell line.

PER.C6, a cell line derived from human embryonic retinal cells transformed with the Adenovirus Type 5 (Ad5) E1A and E1B genes, is used to produce E1-deleted Ad5 vectors such as the MRKAd5 HIV-1 gag vaccine. While whole, live PER.C6 cells are capable of growing as tumours when transplanted subcutaneously into immunodeficient nude mice at a high dosage, the process for vaccine production includes filtration steps and other methods which effectively preclude contamination by intact viable substrate cells. However, because of the neoplastic nature of this cell line, we carried out a series of investigations to assess the tumorigenic risk posed by residuals from the cell substrate in a vaccine. To address concerns about transmission of oncogenic DNA, we demonstrated that purified PER.C6 cellular DNA does not induce tumours in newborn hamsters or nude mice. To address concerns about other potential residuals, including hypothetical adventitious tumour viruses, we demonstrated that a PER.C6 cell lysate and a MRKAd5 HIV-1 gag vaccine produced on PER.C6 cells do not induce tumours in newborn hamsters or newborn rats. These results, in conjunction with the wide panel of viral safety tests performed on these cells, support the safety of the PER.C6 as a cell substrate for vaccine production.

GABAergic synaptic transmission modulates swimming in the ascidian larva.

To examine the role of the amino acid GABA in the locomotion of basal chordates, we investigated the pharmacology of swimming and the morphology of GABA-immunopositive neurones in tadpole larvae of the ascidians Ciona intestinalis and Ciona savignyi. We verified that electrical recording from the tail reflects alternating muscle activity during swimming by correlating electrical signals with tail beats using high-speed video recording. GABA reversibly reduced swimming periods to single tail twitches, while picrotoxin increased the frequency and duration of electrical activity associated with spontaneous swimming periods. Immunocytochemistry for GABA revealed extensive labelling throughout the larval central nervous system. Two strongly labelled regions on either side of the sensory vesicle were connected by an arc of labelled fibres, from which fibre tracts extended caudally into the visceral ganglion. Fibre tracts extended ventrally from a third, more medial region in the posterior sensory vesicle. Two rows of immunoreactive cell bodies in the visceral ganglion extended neurites into the nerve cord, where varicosities were seen. Thus, presumed GABAergic neurones form a network that could release GABA during swimming that is involved in modulating the time course and frequency of periods of spontaneous swimming. GABAergic and motor neurones in the visceral ganglion could interact at the level of their cell bodies and/or through the presumed GABAergic fibres that enter the nerve cord. The larval swimming network appears to possess some of the properties of spinal networks in vertebrates, while at the same time possibly showing a type of peripheral innervation resembling that in some protostomes.

Ultrasound crack detection in a simulated human tooth.

OBJECTIVE: Currently, diagnosis of cracked teeth generally depends upon the overall clinical assessment, or on exclusion of other clinical possibilities, not primarily on the direct identification of cracks themselves. Owing to its short wavelength in hard tissues and associated high resolution, ultrasound has the potential to allow detection of cracks within tooth structure. However, ultrasound detection of dental cracks has not previously been achieved. The purpose was to determine if an ultrasound imaging system was capable of imaging cracks in simulated tooth structure. METHODS: A complete ultrasound system including a novel transducer made of PLZT-98, a novel gallium-indium alloy coupling agent, and customized electronic and digital signal processing (DSP) algorithms was developed for the specific application of optimizing crack detection within teeth. A simulated tooth with a known and uniform internal structure and acoustic properties similar to those of natural enamel and dentin was designed to model a human tooth with a crack located in dentin deep to the dentino-enamel junction (DEJ). The distance between the DEJ and a crack of the simulated tooth were calculated. RESULTS: The system unequivocally distinguished between areas with and without a simulated crack. CONCLUSION: A unique ultrasound dental crack detection system using a novel transducer; a novel coupling agent; and customized electronic and digital signal processing (DSP) algorithms has been validated in a simulated tooth.

Comparison of nevirapine (NVP) resistance in Ugandan women 7 days vs. 6-8 weeks after single-dose nvp prophylaxis: HIVNET 012.

We compared nevirapine (NVP) resistance (NVPR) mutations in maternal plasma 7 days vs. 6-8 weeks after single-dose NVP prophylaxis. In the HIVNET 012 trial, Ugandan women received a single dose of NVP in labor for prevention of HIV-1 mother-to-child transmission. NVPR mutations were detected in 70 (25%) of 279 women 6-8 weeks after NVP. Samples collected 7 days after NVP were analyzed from a subset of those 279 women. Genotyping was performed with the ViroSeq HIV-1 Genotyping System. NVPR was analyzed using paired samples from 7 days and 6-8 weeks after NVP. Sixty-five women had genotyping results obtained for samples collected at both 7 days and 6-8 weeks post-NVP. Twenty-one (32%) of those women had NVPR mutations detected in one or both samples. This included three women with NVPR at 7 days only, seven with NVPR at 6-8 weeks only, and 11 with NVPR at both time points. Eight women had >1 NVPR mutation detected 7 days after NVP. Y181C was the most common NVPR mutation detected at 7 days, whereas K103N was the most common NVPR mutation detected at 6-8 weeks. We conclude that NVPR may be detected in women as early as 7 days after single-dose NVP. Complex patterns of NVPR are detected in some women. The Y181C NVPR mutation often fades from detection by 6-8 weeks. In contrast, the K103N mutation emerges more slowly, but often remains detectable 6-8 weeks after NVP.

Imaging of human tooth enamel using ultrasound.

This paper reports the results of a complete circumferential scan of a human tooth and its underlying dentino-enamel junction using ultrasound at frequencies in the 10-MHz range. The imagery shows clearly a two-dimensional contour of the dentinoenamel junction with a depth and lateral resolution of approximately 100 microm and 750 microm, respectively. The resulting sonograph is compared with an optical micrograph of the same tooth to verify the accuracy of the ultrasonic technique. The results are a significant step toward the biolocation of submillimeter size features within the tooth volume.

Ca2+ signalling and membrane current activated by cADPr in starfish oocytes.

Cyclic ADP-ribose (cADPr) is a second messenger that regulates intracellular free [Ca2+] ([Ca2+](i)) in a variety of cell types, including immature oocytes from the starfish Astropecten auranciacus. In this study, we employed confocal laser scanning microscopy and voltage clamp techniques to investigate the source of the cADPr-elicited Ca2+ wave originating from the cortical Ca2+ patches we have described previously. The Ca2+ swing was accompanied by a membrane current with a reversal potential of approximately +20 mV. Decreasing external Na+ almost abolished the current without affecting the Ca2+ response. Removal of extracellular Ca2+ altered neither the Ca2+ transient nor the ionic current, nor did the holding potential exert any effect on the Ca2+ wave. Both the Ca2+ response and the membrane current were abolished when BAPTA, ruthenium red or 8-NH(2)-cADPr were preinjected into the oocytes, while perfusion with ADPr did not elicit any [Ca2+](i) increase or ionic current. However, elevating [Ca2+](i) by uncaging Ca2+ from nitrophenyl- (NP-EGTA) or by photoliberating inositol 1,4,5-trisphosphate (InsP(3)) induced an ionic current with biophysical properties similar to that elicited by cADPr. These results suggest that cADPr activates a Ca2+ wave by releasing Ca2+ from intracellular ryanodine receptors and that the rise in [Ca2+](i) triggers a non-selective monovalent cation current that does not seem to contribute to the global Ca2+ elevation.

Evidence for a strong surface-plasmon resonance on ErAs nanoparticles in GaAs.

Room-temperature attenuation measurements are made between lambda=0.8 and 10.0 microm on three GaAs epitaxial samples containing layers of ErAs nanoparticles. An asymmetric attenuation peak is observed around 2.5 microm that increases in strength with ErAs density, and is modeled well by a Maxwell-Garnett formulation and semiclassical transport theory. The nanoparticles are assigned a distribution function of oblate spheroids having a minimum volume corresponding to a 1.0-nm sphere. This is consistent with the self-organizing tendency of ErAs in GaAs, and explains the sharp attenuation peak as a spherical-particle surface-plasmon (i.e., Fröhlich) resonance.

Effect of glycine on synaptic transmission at the third order giant synapse of the squids Alloteuthis subulata and Loligo vulgaris.

Intracellular microelectrode recordings were made from presynaptic and postsynaptic regions of the third order giant synapses of the squids Alloteuthis subulata and Loligo vulgaris. Synaptically generated postsynaptic action potential trains, and excitatory postsynaptic potentials (EPSPs) were reversibly decreased by glycine, beta - alanine or taurine while presynaptic action potentials (APs) were unaltered. Glycine was effective in the presence of strychnine (30-50 microM), NMDA (500 microM), AP-5 (50 microM), CPP (100 microM), or MK 801 (which also had no effect on normal synaptic transmission). The glycine effect was reduced reversibly by D-tubocurarine (100 microM) and blocked by reducing extracellular chloride by 50% with propionate. Excitatory postsynaptic currents (EPSCs) were decreased by glycine addition without altering resting membrane conductance. We postulate that glycine or a glycine like substance provides an excitatory postsynaptic input during synaptic stimulation. Bath addition of glycine desensitises these receptors and decreases the amplitude of the EPSPs and EPSCs. Modulation of this synaptic input may provide an effective mechanism to suppress or potentiate synaptic transmission in the squid giant synapse.

Differential sensitivity to calciseptine of L-type Ca(2+) currents in a 'lower' vertebrate (Scyliorhinus canicula), a protochordate (Branchiostoma lanceolatum) and an invertebrate (Alloteuthis subulata).

Voltage-dependent calcium currents in vertebrate (Scyliorhinus canicula), protochordate (Branchiostoma lanceolatum), and invertebrate (Alloteuthis subulata) skeletal and striated muscle were examined under whole-cell voltage clamp. Nifedipine (10 microM) suppressed and cobalt (5 mM) blocked striated/skeletal muscle calcium currents in all of the animals examined, confirming that they are of the L-type class. Calciseptine, a specific blocker of vertebrate cardiac muscle and neuronal L-type calcium currents, was applied (0.2 microM) under whole-cell voltage clamp. Protochordate and invertebrate striated muscle L-type calcium currents were suppressed while up to 4 microM calciseptine had no effect on dogfish skeletal muscle L-type calcium currents. Our results demonstrate the presence of at least two sub-types of L-type calcium current in these different animals, which may be distinguished by their calciseptine sensitivity. We conclude that the invertebrate and protochordate L-type current sub-type that we have examined has properties in common with vertebrate 'cardiac' and 'neuronal' current sub-types, but not the skeletal muscle sub-type of the L-type channel.

Improving the fit of bivariate smoothing splines when estimating longitudinal immunological and virological markers in HIV patients with individual antiretroviral treatment strategies.

CD4+ lymphocyte count and HIV RNA plasma viral load are longitudinally monitored in patients with HIV infection. Because data collection intervals may be unequally spaced and these markers experience high within-patient variability, they may be smoothed before use in subsequent models. Estimation strategies must be able to accommodate the drastic changes in viral load which may occur when an individual's treatment strategy is updated. Because these treatment changes are not regimented, these dynamics cannot be modelled using standard methods. We propose univariate and bivariate cubic smoothing splines to fit CD4+ count and viral load over time. The method is developed using state space equations, and the Kalman filter is used to calculate the log-likelihood. Non-linear optimization is used to obtain the maximum likelihood estimates. A modification of the Kalman filter allows non-informative or diffuse priors at the initial observation. Since treatment changes are expected to alter the shape of the curve, we further extend the Kalman filter to permit greater flexibility in the smoothing spline at these time points. The method produces smoothed estimates of the viral load and CD4+ count curves over time.