Oncolytic vaccinia virus as a vector for therapeutic sodium iodide symporter gene therapy in prostate cancer.

Oncolytic strains of vaccinia virus are currently in clinical development with clear evidence of safety and promising signs of efficacy. Addition of therapeutic genes to the viral genome may increase the therapeutic efficacy of vaccinia. We evaluated the therapeutic potential of vaccinia virus expressing the sodium iodide symporter (NIS) in prostate cancer models, combining oncolysis, external beam radiotherapy and NIS-mediated radioiodide therapy. The NIS-expressing vaccinia virus (VV-NIS), GLV-1h153, was tested in in vitro analyzes of viral cell killing, combination with radiotherapy, NIS expression, cellular radioiodide uptake and apoptotic cell death in PC3, DU145, LNCaP and WPMY-1 human prostate cell lines. In vivo experiments were carried out in PC3 xenografts in CD1 nude mice to assess NIS expression and tumor radioiodide uptake. In addition, the therapeutic benefit of radioiodide treatment in combination with viral oncolysis and external beam radiotherapy was measured. In vitro viral cell killing of prostate cancers was dose- and time-dependent and was through apoptotic mechanisms. Importantly, combined virus therapy and iodizing radiation did not adversely affect oncolysis. NIS gene expression in infected cells was functional and mediated uptake of radioiodide both in vitro and in vivo. Therapy experiments with both xenograft and immunocompetent Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mouse models showed that the addition of radioiodide to VV-NIS-infected tumors was more effective than each single-agent therapy, restricting tumor growth and increasing survival. In conclusion, VV-NIS is effective in prostate cancer models. This treatment modality would be an attractive complement to existing clinical radiotherapy practice.

Refractive index determination by coherence scanning interferometry.

Coherence scanning interferometry is established as a powerful noncontact, three-dimensional, metrology technique used to determine accurate surface roughness and topography measurements with subnanometer precision. The helical complex field (HCF) function is a topographically defined helix modulated by the electrical field reflectance, originally developed for the measurement of thin films. An approach to extend the capability of the HCF function to determine the spectral refractive index of a substrate or absorbing film has recently been proposed. In this paper, we confirm this new capability, demonstrating it on surfaces of silicon, gold, and a gold/palladium alloy using silica and zirconia oxide thin films. These refractive index dispersion measurements show good agreement with those obtained by spectroscopic ellipsometry.

New steady-state quiescent high-confinement plasma in an experimental advanced superconducting tokamak.

A critical challenge facing the basic long-pulse high-confinement operation scenario (H mode) for ITER is to control a magnetohydrodynamic (MHD) instability, known as the edge localized mode (ELM), which leads to cyclical high peak heat and particle fluxes at the plasma facing components. A breakthrough is made in the Experimental Advanced Superconducting Tokamak in achieving a new steady-state H mode without the presence of ELMs for a duration exceeding hundreds of energy confinement times, by using a novel technique of continuous real-time injection of a lithium (Li) aerosol into the edge plasma. The steady-state ELM-free H mode is accompanied by a strong edge coherent MHD mode (ECM) at a frequency of 35-40 kHz with a poloidal wavelength of 10.2 cm in the ion diamagnetic drift direction, providing continuous heat and particle exhaust, thus preventing the transient heat deposition on plasma facing components and impurity accumulation in the confined plasma. It is truly remarkable that Li injection appears to promote the growth of the ECM, owing to the increase in Li concentration and hence collisionality at the edge, as predicted by GYRO simulations. This new steady-state ELM-free H-mode regime, enabled by real-time Li injection, may open a new avenue for next-step fusion development.

Sleep difficulty mediates effects of vasomotor symptoms on mood in younger breast cancer survivors.

OBJECTIVE: Treatment-induced early menopause occurs in > 80% of premenopausal women diagnosed with breast cancer. This study explored the relationship between vasomotor symptoms (VMS), sleep and mood in women aged 40-51 years with non-metastatic breast cancer. METHODS: Cross-sectional study using validated questionnaires (Greene Climacteric scale and Hospital Anxiety and Depression Scale, HADS). Women (n = 114) were recruited from the community and hospital outpatient clinics. Frequency determination and structural equation modeling (SEMod) were used to examine the relationship between the latent variables: VMS, anxiety, and depression, and the indicator variable: difficulty sleeping. RESULTS: Participants' mean age was 47 years and 94% became menopausal after breast cancer diagnosis. Difficulty sleeping was reported by 82% of women with 46% reporting (Likert scale) 'quite a bit/extremely'. Most women reported night sweats (77% of women: 47% reporting 'quite a bit/extremely') and hot flushes (84% of women: 50% reporting 'quite a bit/extremely'). HADS scores indicated clinically relevant depression and anxiety in 98% and 99% of women, respectively. SEMod revealed that VMS contributed to difficulty sleeping (standardized coefficient = 0.54; p < 0.001) and difficulty sleeping mediated the relationship between VMS and anxiety (standardized coefficient = 0.34; p = 0.03). However, difficulty sleeping did not have a significant direct impact on depression (standardized coefficient = -0.03; p = 0.8), although anxiety was a strong predictor of depression (standardized coefficient = 0.83; p = 0.015). CONCLUSIONS: VMS, sleep and mood disturbance are commonly experienced by younger women with breast cancer. Using SEMod, we demonstrate for the first time that VMS may directly influence sleep in these women. VMS may have an indirect effect on mood, partly mediated by sleep difficulty.

Synergistic cytotoxicity of oncolytic reovirus in combination with cisplatin-paclitaxel doublet chemotherapy.

Oncolytic reovirus is currently under active investigation in a range of tumour types. Early phase studies have shown that this agent has modest monotherapy efficacy and its future development is likely to focus on combination regimens with cytotoxic chemotherapy. Indeed, phase I/II clinical trials have confirmed that reovirus can be safely combined with cytotoxic drugs, including a platin-taxane doublet regimen, which is currently being tested in a phase III clinical trial in patients with relapsed/metastatic head and neck cancer. Therefore, we have tested this triple (reovirus, cisplatin, paclitaxel) combination therapy in a panel of four head and neck cancer cell lines. Using the combination index (CI) method, the triple therapy demonstrated synergistic cytotoxicity in vitro in both malignant and non-malignant cell lines. In head and neck cancer cell lines, this was associated with enhanced caspase 3 and 7 cleavage, but no increase in viral replication. In vitro analyses confirmed colocalisation of markers of reovirus infection and caspase 3. Triple therapy was significantly more effective than reovirus or cisplatin-paclitaxel in athymic nude mice. These data suggest that the combination of reovirus plus platin-taxane doublet chemotherapy has significant activity in head and neck cancer and underpin the current phase III study in this indication.

The importance of informed consent in patients with wet age-related macular degeneration considering intravitreal anti-vascular endothelial growth factor treatments.

Retinal pigment epithelial (RPE) tears are now a documented potential complication following the intravitreal injection of anti-vascular endothelial growth factor (VEGF) treatments for neovascular age-related macular degeneration. Patients are often not well consented regarding this risk and thus we retrospectively analyzed the data from all of our patients undergoing this treatment over a six month period. Our findings highlighted the fact that the three patients (out of thirty) who had developed this RPE tear complication were initially all diagnosed with a pigment epithelial detachment (which is a type of macular degeneration in question). Therefore, we have adjusted our informed consent procedure such that all patients with "wet" macular degeneration and especially those with pigment epithelial detachments are now fully consented regarding the risks of the intravitreal treatment, which could potentially damage their vision further.

OX40 and 4-1BB delineate distinct immune profiles in sarcoma.

Systemic relapse after radiotherapy and surgery is the major cause of disease-related mortality in sarcoma patients. Combining radiotherapy and immunotherapy is under investigation as a means to improve response rates. However, the immune contexture of sarcoma is understudied. Here, we use a retrospective cohort of sarcoma patients, treated with neoadjuvant radiotherapy, and TCGA data. We explore therapeutic targets of relevance to sarcoma, using genomics and multispectral immunohistochemistry to provide insights into the tumor immune microenvironment across sarcoma subtypes. Differential gene expression between radioresponsive myxoid liposarcoma (MLPS) and more radioresistant undifferentiated pleomorphic sarcoma (UPS) indicated UPS contained higher transcript levels of a number of immunotherapy targets (CD73/NT5E, CD39/ENTPD1, CD25/IL2RA, and 4-1BB/TNFRSF9). We focused on 4-1BB/TNFRSF9 and other costimulatory molecules. In TCGA data, 4-1BB correlated to an inflamed and exhausted phenotype. OX40/TNFRSF4 and 4-1BB/TNFRSF9 were highly expressed in sarcoma subtypes versus other cancers. Despite OX40 and 4-1BB being described as Treg markers, we identified that they delineate distinct tumor immune profiles. This was true for sarcoma and other cancers. While only a limited number of samples could be analyzed, spatial analysis of OX40 expression identified two diverse phenotypes of OX40+ Tregs, one associated with and one independent of tertiary lymphoid structures (TLSs). Patient stratification is of intense interest for immunotherapies. We provide data supporting the viewpoint that a cohort of sarcoma patients, appropriately selected, are promising candidates for immunotherapies. Spatial profiling of OX40+ Tregs, in relation to TLSs, could be an additional metric to improve future patient stratification.

Continuous improvement of H-mode discharge performance with progressively increasing lithium coatings in the National Spherical Torus Experiment.

Lithium wall coatings have been shown to reduce recycling, improve energy confinement, and suppress edge localized modes in the National Spherical Torus Experiment. Here, we show that these effects depend continuously on the amount of predischarge lithium evaporation. We observed a nearly monotonic reduction in recycling, decrease in electron transport, and modification of the edge profiles and stability with increasing lithium. These correlations challenge basic expectations, given that even the smallest coatings exceeded that needed for a nominal thickness of the order of the implantation range.

Psychophysical functions for perceived and remembered size.

Separate groups of people estimated the sizes of perceived or of remembered objects. In three independent experiments, both sets of data were well fit by power functions, and the exponent was reliably smaller by remembered than for perceived size.

Coloured filters and reading accuracy, comprehension and rate: a placebo-controlled study.

Literature suggests that visuoperceptual deficits not normally assessed by eye examinations may be responsible for certain reading disabilities. Previous studies indicate that the use of nonoptical coloured filters may reduce these deficits and improve reading performance. Present research involved 49 participants with visuo-perceptual reading disabilities. Participants were divided into a control group who received no intervention, a placebo group who received filters in a colour complementary to the individual's optimal colour, and an experimental group who received specifically matched coloured filters. At posttest the experimental group reported statistically significantly fewer visual discomfort symptoms. The remainder of the results were, however, inconsistent. Some potential explanations are explored.

The SSRI citalopram increases the sensitivity of the human circadian system to light in an acute dose.

RATIONALE: Disturbances of the circadian system are common in depression. Though they typically subside when depression is treated with antidepressants, the mechanism by which this occurs is unknown. Despite being the most commonly prescribed class of antidepressants, the effect of selective serotonin reuptake inhibitors (SSRIs) on the human circadian clock is not well understood. OBJECTIVE: To examine the effect of the SSRI citalopram (30 mg) on the sensitivity of the human circadian system to light. METHODS: This study used a double-blind, placebo-controlled, within-subjects, crossover design. Participants completed two melatonin suppression assessments in room level light (~ 100 lx), taking either a single dose of citalopram 30 mg or a placebo at the beginning of each light exposure. Melatonin suppression was calculated by comparing placebo and citalopram light exposure conditions to a dim light baseline. RESULTS: A 47% increase in melatonin suppression was observed after administration of an acute dose of citalopram, with all participants showing more suppression after citalopram administration (large effect, d = 1.54). Further, melatonin onset occurred later under normal room light with citalopram compared to placebo. CONCLUSIONS: Increased sensitivity of the circadian system to light could assist in explaining some of the inter-individual variability in antidepressant treatment responses, as it is likely to assist in recovery in some patients, while causing further disruption for others.

A multi-species powder dropper for magnetic fusion applications.

We present a device for controlled injection of a variety of materials in powder form. The system implements four independent feeder units, arranged to share a single vertical drop tube. Each unit consists of a 80 ml reservoir, coupled to a horizontal linear trough, where a layer of powder is advanced by piezo-electric agitation at a speed proportional to the applied voltage, until it falls into a drop tube. The dropper has been tested with a number of impurities of low (B, BN, C), intermediate (Si, SiC), and high Z (Sn) and a variety of microscopic structures (flakes, spheres, rocks) and sizes (5-200 µm). For low Z materials, drop rates ∼2-200 mg/s have been obtained showing good repeatability and uniformity. A calibrated light-emitting diode (LED)-based flowmeter allows measuring and monitoring the drop rate during operation. The fast time-response of the four feeders allows combination of steady and pulsed injections, providing a flexible tool for controlled-dose, real-time impurity injection in fusion plasmas.

Upgraded flowing liquid lithium limiter for improving Li coverage uniformity and erosion resistance in EAST device.

We report on design and technology improvements for a flowing liquid lithium (FLiLi) limiter inserted into auxiliary heated discharges in the experimental advanced superconducting tokamak device. In order to enhance Li coverage uniformity and erosion resistance, a new liquid Li distributor with homogenous channels was implemented. In addition, two independent electromagnetic pumps and a new horizontal capillary structure contributed to an improvement in the observed Li flow uniformity (from 30% in the previous FLiLi design to >80% in this FLiLi design). To improve limiter surface erosion resistance, hot isostatic press technology was applied, which improved the thermal contact between thin stainless steel protective layers covering the Cu heat sink. The thickness of the stainless steel layer was increased from 0.1 mm to 0.5 mm, which also helped macroscopic erosion resilience. Despite the high auxiliary heating power up to 4.5 MW, no Li bursts were recorded from FLiLi, underscoring the improved performance of this new design.

Acute effects of continuous positive airway pressure on cardiac sympathetic tone in congestive heart failure.

BACKGROUND: Depressed ventricular performance and neurohormonal activation are key pathophysiological features of congestive heart failure (CHF). Although angiotensin-converting enzyme inhibitors and beta-adrenoceptor blockers exert beneficial effects in CHF, mortality remains unacceptably high, and the development of further therapeutic approaches is warranted. Recent data suggest that continuous positive airway pressure (CPAP) may be of benefit in the treatment of CHF, although the mechanism for this action is incompletely understood. METHODS AND RESULTS: In the present study, we examined the effect of short-term CPAP (10 cm H(2)O for 10 minutes) on hemodynamics (Swan Ganz catheter) and total systemic and cardiac sympathetic activity (norepinephrine spillover method) in 14 CHF patients in New York Heart Association class III. The application of CPAP was associated with a fall in cardiac output (4.8+/-0.3 to 4.4+/-0.2 L/min; P<0.05) and a significant reduction in cardiac norepinephrine spillover (370+/-58 to 299+/-55 pmol/min; P<0.05), although total systemic norepinephrine spillover was unchanged. CONCLUSION: The short-term application of CPAP results in an inhibition of cardiac sympathetic nervous activity. Further investigation into the potential value of long-term CPAP in CHF patients is warranted.

Automated linkage analysis in psychiatric disorders.

A genome-wide search for linkage of microsatellite markers to chromosomal loci containing genes responsible for the major psychoses is a laborious task which can be carried out with greater speed and economy by introducing automation to several steps in the procedure. We describe the use of the Automated Linkage Preprocessor (ALP) program for the computer analysis of the waveform generated by fluorescein-labelled markers after electrophoretic separation. (To obtain a copy send a request to A.F. Brown at the below MRC address or use Anonymous FTP to ftp.hgu.mrc.ac.uk. Software is in directory pub/ALP). The program runs on a PC in the Microsoft Windows environment, and is used in conjunction with an automated laser fluorescence (ALF) sequencer (Pharmacia) and its Fragment Manager software to detect and size the PCR products, filter out peaks of fluorescence due to nonallele fragments, and generate genotypes in a format suitable for direct input to standard linkage analysis programs. The method should offer the advantages of speed, accuracy, and reduced cost. Its use in linkage studies in a large family with manic-depressive illness is discussed.

"Glaucoma affecting each crystalline lens": a long-lost manuscript by Dr. William Mackenzie.

Dr. William Mackenzie was one of the great pioneers of British ophthalmology in the 19th century. We present a newly-discovered manuscript in which Mackenzie described how he performed surgery for bilateral nuclear sclerosis of the lens, in 1842-1843. This case became the focus for a discussion of the nature of "cataract" and "glaucoma" in the fourth edition of Mackenzie's great work, A practical treatise on diseases of the eye. Mackenzie is generally remembered as a great compiler of knowledge, but the text Mackenzie built around this case shows him pursuing original arguments based on his own observation. This case report gives us a vignette of Mackenzie that illustrates aspects of Mackenzie's character and achievements in an intimate way, and it dramatizes in a lively manner how some of the most fundamental concepts in ophthalmology evolved.

Comparison of sparfloxacin and ciprofloxacin in the treatment of community-acquired acute uncomplicated urinary tract infection in women. Sparfloxacin Multicenter Uncomplicated Urinary Tract Infection Study Group.

Urinary tract infection (UTI) is a common illness, with > or =30% of all women experiencing a UTI during their lifetime. Less than a decade ago, the standard therapy for acute uncomplicated UTIs involved treatment with > or =7 days of an antibacterial agent, but recent studies using a variety of newly introduced antibiotics, including the fluoroquinolones, have demonstrated that a 1- to 5-day treatment regimen can be equally effective. This randomized, double-masked, multicenter study was conducted to compare the efficacy and tolerability of a single dose of sparfloxacin with those of a 3-day regimen of sparfloxacin and a 7-day regimen of ciprofloxacin in the treatment of women with community-acquired acute uncomplicated urinary tract infection. A total of 1175 women were enrolled; 395 received sparfloxacin as a single 400-mg dose on day 1, 394 received sparfloxacin as a 400-mg loading dose on day 1 followed by 200 mg once daily for 2 additional days, and 386 received ciprofloxacin 250 mg twice daily for 7 days. Patients were comparable with respect to demographic characteristics and underlying conditions. A total of 954 patients were clinically assessable; 490 of these were also bacteriologically assessable. All patients treated were included in the tolerability analysis. Escherichia coli (75.4%), Klebsiella pneumoniae (4.9%), Enterococcus faecalis (4.6%), and Staphylococcus saprophyticus (4.1%) were the most commonly isolated organisms. In the all-treated population, clinical success was achieved 5 to 9 days after therapy in 91.8%, 92.2%, and 91.6% of patients in the single-dose sparfloxacin, 3-day sparfloxacin, and 7-day ciprofloxacin groups, respectively; bacteriologic success was observed in 91.7%, 92.6%, and 96.6% of those in the 3 groups. Sustained clinical success rates 4 to 6 weeks after therapy were 76.6%, 80.2%, and 79.5% in the single-dose sparfloxacin, 3-day sparfloxacin, and 7-day ciprofloxacin groups, respectively; sustained bacteriologic success rates were 80.7%, 90.1%, and 92.6%. The most common adverse events were nausea, headache, vaginal thrush, dizziness, and diarrhea; >92% of adverse events were mild or moderate in severity. The 2 drugs had comparable frequencies of adverse events, except for photosensitivity, which occurred in 3.3% of the 3-day sparfloxacin group, 1.3% of the single-dose sparfloxacin group, and 0.3% of the ciprofloxacin group (P = 0.005). The 3-day sparfloxacin regimen was effective and well tolerated. The initial response to single-dose sparfloxacin treatment was comparable to the response to the other 2 regimens, but the single-dose regimen proved less effective over time, with higher rates of clinical recurrence and bacteriologic relapse. Sparfloxacin provides an alternative to ciprofloxacin for patients with acute uncomplicated urinary tract infection who are not at risk for photosensitivity reactions or adverse events associated with a prolonged corrected QT interval.

Magnetoencephalography and stereopsis: rhythmic cortical activity in humans recorded over the parieto-occipital cortex.

We have studied human stereopsis by analysing magnetoencephalographic signals during the presentation of stereograms using frequency analysis. The study of synchronised firing of cortical neurones is a new way of understanding information processing in the brain and it is hypothesised that frequencies greater than 35 Hz are used for higher-order processing. We report the response of cortical neurones involved in stereopsis recorded from over the occipital and parietal cortices using a single channel axial superconducting quantum interference device neuromagnetometer. Our main result was increased cortical activity in the gamma-band at frequencies apparently related to stereopsis and the perception of depth. Our results are consistent with reports in the literature that suggest that frequencies above 40 Hz are involved in attention, pattern recognition and higher order visual activity.

Genetic heterogeneity in familial exudative vitreoretinopathy; exclusion of the EVR1 locus on chromosome 11q in a large autosomal dominant pedigree.

BACKGROUND/AIMS: Familial exudative vitreoretinopathy (FEVR) is associated with mutations in the Norrie disease gene in X linked pedigrees and with linkage to the EVR1 locus at 11q13 in autosomal dominant cases. A large autosomal dominant FEVR family was studied, both clinically and by linkage analysis, to determine whether it differed from the known forms of FEVR. METHODS: Affected members and obligate gene carriers from this family were examined by slit lamp biomicroscopy, indirect ophthalmoscopy, and in some cases fluorescein angiography. Patient DNAs were genotyped for markers at the EVR1 locus on chromosome 11q13. RESULTS: The clinical evaluation in this family is consistent with previous descriptions of FEVR pedigrees, but linkage analysis proves that it has a form of FEVR genetically distinct from the EVR1 locus on 11q. CONCLUSION: This proves that there are at least three different loci associated with comparable FEVR phenotypes, a situation similar to that existing for many forms of retinal degeneration.