Liquid compound refractive X-ray lens.

We introduce the concept of a liquid compound refractive X-ray zoom lens. The lens is generated by pumping a suitable liquid lens material like water, alcohol or heated lithium through a line of nozzles each forming a jet with the cross section of lens elements. The system is housed, so there is a liquid-circulation. This lens can be used in white beam at high brilliance synchrotron sources, as radiation damages are cured by the continuous reformation of the lens. The focal length can be varied by closing nozzles, thus reducing the number of lens elements in the beam.

Cochrane's Linked Data Project: How it Can Advance our Understanding of Surrogate Endpoints.

Cochrane has developed a linked data infrastructure to make the evidence and data from its rich repositories more discoverable to facilitate evidence-based health decision-making. These annotated resources can enhance the study and understanding of biomarkers and surrogate endpoints.

Correction: S1PR1 drives a feedforward signalling loop to regulate BATF3 and the transcriptional programme of Hodgkin lymphoma cells.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

X-ray zoom lens allows for energy scans in X-ray microscopy.

We introduce a new design and development of a compound refractive X-ray zoom lens for energy scans in X-ray microscopy. Energy scans are, in principle, equivalent to radial scans in the reciprocal space for X-ray diffraction. Thanks to the absence of sample or detector motions, energy scans are better suited for microscopy, which requires high stability. In addition, close to the absorption edge of an element, energy scans can yield chemical information when coupled with resonant effects in full field diffraction X-ray microscopy (FFDXM) or X-ray absorption near edge structure (XANES) microscopy. Here, we demonstrate the concept by using a customized compound refractive X-ray zoom lens for 11 keV near the Ge Kα-edge. The working distance and magnification were kept constant during the energy scans by adapting the lens composition on switchable zoom lens fingers. This alleviates the need to reposition the lens while changing the energy and makes quantitative analysis more convenient for FFDXM. The fabricated zoom lens was characterized and proven suitable for the proposed measurement.

Optimizing illumination for full field imaging at high brilliance hard X-ray synchrotron sources.

A new technique is presented to overcome beam size limitation in full field imaging at high brilliance synchrotron sources using specially designed refractive X-ray optics. These optics defocus the incoming beam in vertical direction and reshape the intensity distribution from a Gaussian to a more desirable top-hat-shaped profile at the same time. With these optics X-ray full-field imaging of extended objects becomes possible without having to stack several scans or applying a cone beam geometry in order to image the entire specimen. For in situ experiments in general and for diffraction limited sources in particular this gain in field of view and the optimization of the intensity distribution is going to be very beneficial.

Population-based analysis of ocular Chlamydia trachomatis in trachoma-endemic West African communities identifies genomic markers of disease severity.

BACKGROUND: Chlamydia trachomatis (Ct) is the most common infectious cause of blindness and bacterial sexually transmitted infection worldwide. Ct strain-specific differences in clinical trachoma suggest that genetic polymorphisms in Ct may contribute to the observed variability in severity of clinical disease. METHODS: Using Ct whole genome sequences obtained directly from conjunctival swabs, we studied Ct genomic diversity and associations between Ct genetic polymorphisms with ocular localization and disease severity in a treatment-naïve trachoma-endemic population in Guinea-Bissau, West Africa. RESULTS: All Ct sequences fall within the T2 ocular clade phylogenetically. This is consistent with the presence of the characteristic deletion in trpA resulting in a truncated non-functional protein and the ocular tyrosine repeat regions present in tarP associated with ocular tissue localization. We have identified 21 Ct non-synonymous single nucleotide polymorphisms (SNPs) associated with ocular localization, including SNPs within pmpD (odds ratio, OR = 4.07, p* = 0.001) and tarP (OR = 0.34, p* = 0.009). Eight synonymous SNPs associated with disease severity were found in yjfH (rlmB) (OR = 0.13, p* = 0.037), CTA0273 (OR = 0.12, p* = 0.027), trmD (OR = 0.12, p* = 0.032), CTA0744 (OR = 0.12, p* = 0.041), glgA (OR = 0.10, p* = 0.026), alaS (OR = 0.10, p* = 0.032), pmpE (OR = 0.08, p* = 0.001) and the intergenic region CTA0744-CTA0745 (OR = 0.13, p* = 0.043). CONCLUSIONS: This study demonstrates the extent of genomic diversity within a naturally circulating population of ocular Ct and is the first to describe novel genomic associations with disease severity. These findings direct investigation of host-pathogen interactions that may be important in ocular Ct pathogenesis and disease transmission.

S1PR1 drives a feedforward signalling loop to regulate BATF3 and the transcriptional programme of Hodgkin lymphoma cells.

The Hodgkin/Reed-Sternberg cells of classical Hodgkin lymphoma (HL) are characterised by the aberrant activation of multiple signalling pathways. Here we show that a subset of HL displays altered expression of sphingosine-1-phosphate (S1P) receptors (S1PR)s. S1P activates phosphatidylinositide 3-kinase (PI3-K) in these cells that is mediated by the increased expression of S1PR1 and the decreased expression of S1PR2. We also showed that genes regulated by the PI3-K signalling pathway in HL cell lines significantly overlap with the transcriptional programme of primary HRS cells. Genes upregulated by the PI3-K pathway included the basic leucine zipper transcription factor, ATF-like 3 (BATF3), which is normally associated with the development of dendritic cells. Immunohistochemistry confirmed that BATF3 was expressed in HRS cells of most HL cases. In contrast, in normal lymphoid tissues, BATF3 expression was confined to a small fraction of CD30-positive immunoblasts. Knockdown of BATF3 in HL cell lines revealed that BATF3 contributed to the transcriptional programme of primary HRS cells, including the upregulation of S1PR1. Our data suggest that disruption of this potentially oncogenic feedforward S1P signalling loop could provide novel therapeutic opportunities for patients with HL.

Miniaturized compound refractive X-ray zoom lens.

We introduce the concept of a miniaturized compound refractive X-ray zoom lens consisting of SU-8 lenses fabricated by deep X-ray lithography. The focal length can be varied by changing the number of lens elements placed in the beam. We use suitable actuators to move single lens elements reversibly out of the beam. The X-ray zoom lens can accept different X-ray energies while keeping a fixed working distance, or vary the focal distance for a fixed energy. The latter is useful in tuning the magnification factor in full field microscopy.

Follicular trachoma and trichiasis prevalence in an urban community in The Gambia, West Africa: is there a need to include urban areas in national trachoma surveillance?

OBJECTIVES: Urban areas are traditionally excluded from trachoma surveillance activities, but due to rapid expansion and population growth, the urban area of Brikama in The Gambia may be developing social problems that are known risk factors for trachoma. It is also a destination for many migrants who may be introducing active trachoma into the area. This study aimed to determine the prevalence and risk factors for follicular trachoma and trichiasis in Brikama. METHODS: A community-based cross-sectional prevalence survey including 27 randomly selected households in 12 randomly selected enumeration areas (EAs) of Brikama. Selected households were offered eye examinations, and the severity of trachoma was graded according to WHO's simplified grading system. Risk factor data were collected from each household via a questionnaire. RESULTS: The overall prevalence of trachomatous inflammation-follicular (TF) in children aged 1-9 years was 3.8% (95% CI 2.5-5.6), and the overall prevalence of trichiasis in adults aged ≥15 years was 0.46% (95% CI 0.17-1.14). EA prevalence of TF varied from 0% to 8.4%. The major risk factors for TF were dirty faces (P < 0.01, OR = 9.23, 95% CI 1.97-43.23), nasal discharge (P = 0.039, OR = 5.11, 95% CI 1.08-24.10) and residency in Brikama for <1 year (P = 0.047, OR = 7.78, 95% CI 1.03-59.03). CONCLUSIONS: Follicular trachoma can be considered to have been eliminated as a public health problem in Brikama according to WHO criteria. However, as the prevalence in some EAs is >5%, it may be prudent to include Brikama in surveillance programmes. Trichiasis remains a public health problem (>0.1%), and active case finding needs to be undertaken.

Anaemia and malnutrition in children aged 0-59 months on the Bijagós Archipelago, Guinea-Bissau, West Africa: a cross-sectional, population-based study.

BACKGROUND: Childhood malnutrition is the leading risk factor for the global burden of disease. Guinea-Bissau is a politically unstable country with high levels of childhood malnutrition and mortality. AIM: To determine the nutritional status of children on three remote islands of the Bijagós Archipelago, Bubaque, Rubane and Soga, and to identify factors associated with malnutrition and anaemia in this population in order to provide a baseline for future public health interventions. METHODS: A cross-sectional, population-based, door-to-door household survey of randomly selected households was undertaken to collect data on children aged 0-59 months (n = 872). Dietary information was collected using a validated questionnaire. Anthropometric measurements were collected using World Health Organization techniques. Capillary blood samples were analysed using a Hemocue®, with anaemia defined as Hb<11 g/dl. RESULTS: The prevalences of stunted, wasted and underweight children were 21.8%, 9.4% and 3.7%, respectively. These figures indicate moderate chronic malnutrition. The significant predictor variables for stunting were: age in months (OR 1.03), rural residence (OR 2.32), anaemia (OR 3.55) and residence on Soga island (OR 0.44). Stunting was more prevalent in males (25.4%) than in females (18.6%) (P = 0.03). The prevalence of anaemia was 80.2%. Age (OR 0.96), male gender (OR 1.81) and stunting (OR 2.87) were significant predictors. The Minimum Acceptable Diet was achieved by only 8.7% of children. CONCLUSION: The prevalence of malnutrition on the Bijagós Archipelago is less than half that on the mainland. This study is the first to determine the prevalence of anaemia in Guinea-Bissau, which, at 80.2%, is of severe public health concern. Future research should focus on the aetiology of stunting and anaemia, especially the contribution of infectious diseases and mother-child interaction. Iron supplementation should be strongly considered in this population.

Spatially and polarization resolved plasmon mediated transmission through continuous metal films.

The experimental demonstration and characterization is made of the plasmon-mediated resonant transmission through an embedded undulated continuous thin metal film under normal incidence. 1D undulations are shown to enable a spatially resolved polarisation filtering whereas 2D undulations lead to spatially resolved, polarization independent transmission. Whereas the needed submicron microstructure lends itself in principle to CD-like low-cost mass replication by means of injection moulding and embossing, the present paper demonstrates the expected transmission effects on experimental models based on metal-coated photoresist gratings. The spectral and angular dependence in the neighbourhood of resonance are investigated and the question of the excess losses exhibited by surface plasmons is discussed.

Invasive lobular carcinoma of the breast presenting successively with colonic and gastric metastases.

Involvement of the gastrointestinal tract by metastases from invasive lobular carcinoma of the breast is well recognised. We report a unique case where, four years after the initial management of the primary breast disease, the patient developed colonic metastases followed by a disease-free interval of two years and then presented with gastric metastases. The patient responded successfully to first- and second-line chemotherapeutic agents on both occasions and is currently being maintained on third-line hormonal therapy.

Probing subtle differences in the hydrogen exchange behavior of variants of the human alpha-lactalbumin molten globule using mass spectrometry.

The hydrogen-exchange behavior of the low-pH molten globule of human alpha-lactalbumin, containing all four disulfides, has been examined and compared with that of a single disulfide variant, [28-111] alpha-lactalbumin, and of a series of proline variants of [28-111] alpha-lactalbumin. The small differences in hydrogen-exchange protection exhibited by these partially folded species were compared by mixing two or more proteins and monitoring their exchange simultaneously using mass spectrometry. The effect of single proline mutations within each alpha-domain helix on hydrogen-exchange protection has been investigated using six proline variants of [28-111] alpha-lactalbumin, L11P, L12P, M30P, I95P, K108P and Q117P. The results show that proline mutations in the A, B, C and D alpha-helices lead to a loss of hydrogen-exchange protection for residues in the local helix without perturbing hydrogen-exchange protection in other regions of the protein. Thus, local unfolding of the A, B, C and D helices does not significantly alter the packing and solvent accessibility of other regions of the molten globule. By contrast, introduction of a proline residue in the C-terminal 3(10) helix produces a larger and more widespread loss of hydrogen-exchange protection, demonstrating that longer-range perturbations of the molten globule have occurred. Thus, residues in this C-terminal region must be involved in contacts that are critical for the stabilisation of the compact molten globule structure.

Trastuzumab: designer drug or fashionable fad?

Trastuzumab (Herceptin) is the first monoclonal antibody to be approved for the treatment of a solid tumour and is directed against the c-erb-B2 receptor. c-erb-B2 is a member of the epidermal growth factor family and approximately 25% of breast cancers express such receptors, which appear to confer a poorer prognosis and may be an indicator of resistance to cytotoxic chemotherapy. This review assesses the mechanisms of action of trastuzumab, discusses the measurement of the HER-2/neu gene and its products, and describes the preclinical and clinical studies that have been instrumental to date in the emergence of trastuzumab in clinical practice.

Protein folding and interactions revealed by mass spectrometry.

Mass spectrometry is capable of examining very large, dynamic proteins and this ability, coupled with its relatively high throughput and low sample requirements, is reflected by its increasing importance for the characterisation of protein structure. Recent developments in mass spectrometry, in particular the refinement of the electrospray process and its coupling with time-of-flight mass analysis, mean that it is poised to contribute not only as a complementary tool but also with a defined role in many areas of chemical biology.

Mechanistic studies of the folding of human lysozyme and the origin of amyloidogenic behavior in its disease-related variants.

The unfolding and refolding properties of human lysozyme and two amyloidogenic variants (Ile56Thr and Asp67His) have been studied by stopped-flow fluorescence and hydrogen exchange pulse labeling coupled with mass spectrometry. The unfolding of each protein in 5.4 M guanidine hydrochloride (GuHCl) is well described as a two-state process, but the rates of unfolding of the Ile56Thr variant and the Asp67His variant in 5.4 M GuHCl are ca. 30 and 160 times greater, respectively, than that of the wild type. The refolding of all three proteins in 0.54 M GuHCl at pH 5.0 proceeds through persistent intermediates, revealed by multistep kinetics in fluorescence experiments and by the detection of well-defined populations in quenched-flow hydrogen exchange experiments. These findings are consistent with a predominant mechanism for refolding of human lysozyme in which one of the structural domains (the alpha-domain) is formed in two distinct steps and is followed by the folding of the other domain (the beta-domain) prior to the assembly of the two domains to form the native structure. The refolding kinetics of the Asp67His variant are closely similar to those of the wild-type protein, consistent with the location of this mutation in an outer loop of the beta-domain which gains native structure only toward the end of the refolding process. By contrast, the Ile56Thr mutation is located at the base of the beta-domain and is involved in the domain interface. The refolding of the alpha-domain is unaffected by this substitution, but the latter has the effect of dramatically slowing the folding of the beta-domain and the final assembly of the native structure. These studies suggest that the amyloidogenic nature of the lysozyme variants arises from a decrease in the stability of the native fold relative to partially folded intermediates. The origin of this instability is different in the two variants, being caused in one case primarily by a reduction in the folding rate and in the other by an increase in the unfolding rate. In both cases this results in a low population of soluble partially folded species that can aggregate in a slow and controlled manner to form amyloid fibrils.

Species- and sex-related differences in metabolism of trichloroethylene to yield chloral and trichloroethanol in mouse, rat, and human liver microsomes.

Trichloroethylene (TRI) has been shown to cause a variety of tumors, particularly in mouse liver and lung and rat kidney. However, a clear association between exposure to TRI and cancer development in humans has not been established. Because TRI metabolism by cytochrome P450s has been implicated in the mechanisms of TRI-induced carcinogenicity in mice, the purpose of the present study was to characterize the kinetics of TRI oxidation in male and female mouse, rat, and human liver microsomes to possibly allow for a better assessment of human risk. Methods were developed to detect and quantitate chloral, trichloroethanol, trichloroacetic acid, dichloroacetic acid, chloroacetic acid, glyoxylic acid, and oxalic acid, known TRI metabolites in rodents or humans. However, only chloral and its further metabolite, trichloroethanol, were consistently detected in the various liver microsomes in the presence of NADPH. Chloral was the major metabolite detected, and its levels were species- and sex-dependent; the amounts of trichloroethanol detected were also species- and sex-dependent but never exceeded 15% of total metabolites. Double-reciprocal plots of metabolite formation with male and female rat and human liver microsomes indicated biphasic kinetics, but this trend was not observed with microsomes from male or female mouse liver. The Vmax data are consistent, with male and female mice being more susceptible to TRI-induced liver carcinogenicity than male rats. However, the Vmax/Km ratios in male and female rat liver microsomes, in comparison with the male mouse liver microsomes, did not correlate with tumor incidences in these tissues. Furthermore, as only two out of six human liver samples examined exhibited Vmax/Km ratios similar or higher than the ratio obtained with male mouse liver, humans may vary in their toxic response after TRI exposure.

Radiotherapy in patients with cardiac pacemakers.

Patients with permanent cardiac pacemakers occasionally require radiotherapy. Therapeutic irradiation may cause pacemakers to malfunction due to the effects of ionizing radiation or electromagnetic interference. Modern pacemakers, using complementary metal oxide semiconductor (CMOS) circuitry, differ from older bipolar semiconductor devices both in their sensitivity to damage and the types of malfunction observed. The mechanisms and types of radiotherapy-induced pacemaker malfunction are described and in vitro and in vivo studies of pacemaker irradiation are reviewed. Some simple precautions are recommended during the planning and administration of radiotherapy to minimize the risk of harm to patients with pacemakers.

Multiple sclerosis in island populations: prevalence in the Bailiwicks of Guernsey and Jersey.

The aim of this study was to establish for the first time the prevalence of multiple sclerosis in the Bailiwicks of Guernsey and Jersey, as representing the most southerly part of the British Isles. All patients with multiple sclerosis in the Channel Islands resident on prevalence day were identified by contacting all medical practices, Multiple Sclerosis, and Action Research for Multiple Sclerosis societies by letter and visits. The crude overall prevalence rates were 113/100,000 (95% confidence interval (95% CI) 90.3-135.7) and 86.7/100,000 (95% CI 63.3-110.0) for the Bailiwicks of Jersey and Guernsey respectively. When standardised to the age and sex structure of a previously reported Northern Ireland population the standardised prevalence ratios were 120.2/100,000 (95% CI 96.0-144.3) for Jersey and 95.6/100,000 (95% CI 69.9-121.3) for the Bailiwick of Guernsey. When compared with recent studies in the northern United Kingdom the prevalence rates for multiple sclerosis in the Channel Islands lend some support to the proposed latitudinal gradient in the British Isles although the standardised prevalence ratio in the Bailiwick of Jersey is similar to those found in recent studies of southern Britain. The standardised prevalence rates of probable and definite multiple sclerosis for the male populations were 37.3/100,000 (95% CI 17.9-56.7) for the Bailiwick of Guernsey and 45.5/100,000 (95% CI 26.3-64.7) for the Bailiwick of Jersey whereas the standardised prevalence rates for the female populations were 97.5/100,000 (95% CI 73.9-143.5) and 139.5/100,000 (95% CI 112.6-181.2) respectively. Thus there is a striking and unexplained 43% higher prevalence of probable and definite multiple sclerosis in the female population of Jersey compared with that of the Bailiwick of Guernsey. This seems to be due to an unusually low prevalence of the disease among the female population of the Bailiwick of Guernsey compared with that of the United Kingdom mainland.