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1.  Architecture of the Outer Membrane of Escherichia coli III. Protein-Lipopolysaccharide Complexes in Intramembraneous Particles 
Journal of Bacteriology  1978;134(3):1089-1098.
In a previous paper (A. Verkleij, L. van Alphen, J. Bijvelt, and B. Lugtenberg, Biochim. Biophys. Acta 466:269-282, 1977) we have hypothesized that particles on the outer fracture face of the outer membrane ([Formula: see text]), with corresponding pits on the inner fracture face of the outer membrane ([Formula: see text]), consist of lipopolysaccharide (LPS) aggregates stabilized by divalent cations and that they might contain protein and/or phospholipid. In the present paper the roles of LPS, cations, and proteins in these [Formula: see text] particles are described more extensively, using a strain that lacks the major outer membrane proteins, b, c, and d (b− c− d−), and has a reduction in the number of [Formula: see text] particles of 75%. To study the role of divalent cations in the formation of [Formula: see text] particles, these b− c− d− cells were grown or incubated with Ca2+, Mg2+, or putrescine. The presence of Ca2+ resulted in the appearance of many [Formula: see text] particles and [Formula: see text] pits. Mg2+ and putrescine were less effective than Ca2+. Introduction of these particles was not accompanied by alterations in the relative amounts of LPS and cell envelope proteins. Ca2+ treatment of a heptoseless derivative of a b− c− d− strain did not result in morphological changes. Incubation of Ca2+-treated cells with ethylenediaminetetraacetate caused the disappearance of the introduced particles as well as the release of more than 60% of the cellular LPS. These results strongly support the hypothesis that LPS is involved in the formation of [Formula: see text] particles and [Formula: see text] pits. The roles of various outer membrane proteins in the formation of [Formula: see text] particles were studied by comparing the freeze-fracture morphology of b− c− d− cells with that of cells which contain one of the outer membrane proteins b, c, d, and e or the receptor protein for bacteriophage lambda. The results showed that the presence of any of these five proteins in a b− c− d− background resulted in a large increase in the number of [Formula: see text] particles and [Formula: see text] pits, indicating that these proteins are, independent of each other, involved in the formation of [Formula: see text] particles and [Formula: see text] pits. The simplest explanation for the results is that in wild-type cells each particle consists of LPS complexed with some molecules of a single protein species, stabilized by either divalent cations or polyamines. It is hypothesized that the outer membrane of the wild-type cell contains a heterogeneous population of particles, of which 75% consists of protein b-LPS, protein c-LPS, and protein d-LPS particles. A function of these particles as aqueous pores is proposed.
PMCID: PMC222359  PMID: 350838
2.  Miniature Grating for Spectrally-Encoded Endoscopy 
Lab on a chip  2013;13(9):1810-1816.
Spectrally-encoded endoscopy (SEE) is an ultraminiature endoscopy technology that acquires high-definition images of internal organs through a sub-mm endoscopic probe. In SEE, a grating at the tip of the imaging optics diffracts the broadband light into multiple beams, where each beam with a distinctive wavelength is illuminated on a unique transverse location of the tissue. By encoding one transverse coordinate with the wavelength, SEE can image a line of the tissue at a time without using any beam scanning devices. This feature of the SEE technology allows the SEE probe to be miniaturized to sub-mm dimensions. While previous studies have shown that SEE has the potential to be utilized for various clinical imaging applications, the translation of SEE for medicine has been hampered by challenges in fabricating the miniature grating inherent to SEE probes. This paper describes a new fabrication method for SEE probes. The new method uses a soft lithographic approach to pattern a high-aspect-ratio grating at the tip of the miniature imaging optics. Using this technique, we have constructed a 500-μm-diameter SEE probe. The miniature grating at the tip of the probe had a measured diffraction efficiency of 75%. The new SEE probe was used to image a human finger and formalin fixed mouse embryos, demonstrating the capability of this device to visualize key anatomic features of tissues with high image contrast. In addition to providing high quality imaging SEE optics, the soft lithography method allows cost-effective and reliable fabrication of these miniature endoscopes, which will facilitate the clinical translation of SEE technology.
PMCID: PMC3734537  PMID: 23503940
3.  An automated calibration method for non-see-through head mounted displays 
Journal of Neuroscience Methods  2011;199(2):328-335.
► Correctly calibrating a head-mounted display (HMD) is critical for the kinds of virtual reality applications used by visual neuroscientists. ► We propose a method that produces these calibrations accurately and quickly. ► Unlike methods proposed by others, ours requires no error-prone human judgements. ► Our method permits the collection of large numbers of samples for the calibration data. We show how number of samples affects calibration accuracy. ► Can be used for the more popular non-see-through HMDs, which, traditionally, have been neglected. Existing calibration techniques work only with optical-see-through HMDs.
Accurate calibration of a head mounted display (HMD) is essential both for research on the visual system and for realistic interaction with virtual objects. Yet, existing calibration methods are time consuming and depend on human judgements, making them error prone, and are often limited to optical see-through HMDs. Building on our existing approach to HMD calibration Gilson et al. (2008), we show here how it is possible to calibrate a non-see-through HMD. A camera is placed inside a HMD displaying an image of a regular grid, which is captured by the camera. The HMD is then removed and the camera, which remains fixed in position, is used to capture images of a tracked calibration object in multiple positions. The centroids of the markers on the calibration object are recovered and their locations re-expressed in relation to the HMD grid. This allows established camera calibration techniques to be used to recover estimates of the HMD display's intrinsic parameters (width, height, focal length) and extrinsic parameters (optic centre and orientation of the principal ray). We calibrated a HMD in this manner and report the magnitude of the errors between real image features and reprojected features. Our calibration method produces low reprojection errors without the need for error-prone human judgements.
PMCID: PMC3142613  PMID: 21620891
Head mounted display; Non-see-through; Calibration; Photogrammetry; Immersive virtual reality
4.  Thank you for the privilege 
Thank you for the privilege to serve as the EFOST President.
I am deeply humbled for having been selected to serve as the new President of EFOST: this is not for the work that I have undertaken, but for what others around me have done.
I hope that my past duties as President of BOSTAA, and as president of the Sports and Exercise Medicine of the Royal Society of Medicine will help me in performing these my new duties.
It all started in 1992, and the EFOST is now just leaving its adolescent phase, with all its teenager problems.
There is truth in Newton’s quote about standing on the shoulders of giants. Francois, you and the other leaders at EFOST have generated the momentum to keep moving EFOST forward, and the wisdom to keep it moving in the right direction. We all benefited from your contributions, dedication and volunteerism.
To step into this role feels a little like steering a train. EFOST operates under a strategic plan which sets our direction and controls how the changing succession of leaders navigates. This plan is critical to helping us maintain focus, direction, and purpose.
It is crucial that we focus on our strategic direction. However, we must continue to monitor the environment around us. We must recognize the changing influences so that we can respond appropriately. Europe is in a state of flux, with great challenges, both scientifically and economically. Strategically, we recognized all this a while ago, and we have tried, and succeeded, to be inclusive. The policy has worked, and we have embraced, and we have been embraced, by several countries during Dr Kelberine’s tenure. I can only thank him and the Board for this vision, and can confirm that I wish this train to continue to move in this direction.
A train can only move if it is on the right tracks: I look forward to work with the great engineers of the organization, and welcome the help of the Board of Trustees to keep us on track.
EFOST was born as a get together of a group of friends, and is the baby that was born from the ideas and ideals of several individuals who are in this room today. To them, my thanks for such ideas and ideals, and an assurance: I wish to uphold them. EFOST will need to move forward, and to ensure that the needs of the Sports Trauma Societies which form, sustain, foster and nurture it are satisfied. For this, one of the charges given to me was to change the bylaws. The process was thorny, but the results have been here for all to see: a flexible, dynamic Executive Board, and a Board at Large which is really representative of all Europe. From you, I expect support. To you, I offer dedication.
The life of a President is often lonely. I am a social animal, and I do not wish to be lonely. I intend to use the help and advice of my Past President, Francois, and to have the support of my Vice President, Gernot. I take this opportunity to thank them in advance, and to apologise to them in advance: I know that it is difficult to work with me. I want things yesterday, and, despite 28 years outside of Italy, my Italian quick fire temper can still surface.
EFOST is a great organization, and it has forged great links. You have all seen how the work that Burt has undertaken and the endless meetings that Francois has held have borne fruits: the EFOST-AOSSM traveling fellowship is now a reality, and the support given by all of you on the Board has been superb: many thanks.
One of our Past Presidents, Paco Biosca, is now the Chief Medical Officer of Chelsea: with him, we have succeeded in establishing a football Team Physician fellowship, and we look forward to strengthening these ties.
More on fellowships during the years of my tenure. But remember: it will not be my doing, it will be the work of all of you, of all of us.
EFOST will need to speak with one voice to the world and the sister organizations. In Europe, we have all too often projected the wrong image of weak leadership and of having more than one train controller. The work that Francois has undertaken has ensured that everybody on the Executive Board sang from the same hymn sheet, and that the front that EFOST presents is united and strong. I intend to continue along these lines: too many at the helm is never too good. Each two years, there can only be one.
No doubt somebody and some organizations will feel challenged. Let me remind all of you that EFOST was never on a conquest trip: EFOST wants to build bridges, not to burn them. EFOST wants to have friends, not enemies. EFOST wants a friendly efficient network, not destructive wars.
We are grateful to our mother, EFORT, and we thank it for its support.
We are close to our sister organisation, ESSKA, and we welcome its President to our Congress: Thank you, Joao. ISAKOS has graced us with unending support: we thank Philippe Neyret, the President Elect, for having graced us with such great scientific input.
ECOSEP is a natural sister organisation and ally: Nikos, you are welcome amongst us today.
Communication is always important: my thanks will have to be conveyed to Dr Doral and Dr Mann and their team for the Newsletter. Only if you have never read it will you ignore the endless hours that Mahmut and Gideon put into it: to them, my vote of thanks.
A scientific organization cannot progress without a journal. You all know about Muscles, Ligaments and Tendons Journal (MLTJ), the official journal of EFOST and ISMuLT. I intend to continue to be the Chief Editor of MLTJ, and I can just see the challenges ahead. Let me tell you: the first two years have been hard, and only now we are starting to see the evidence of the hard work that my Associate Editor, Dr Oliva, has undertaken. It is a baby. Its nourishing milk is the high quality work that it publishes. Unless EFOST and its members nurture it, it will not thrive. Unless we send work to it, it will not flourish. Unless we find funds to keep the spirit of EFOST going through it, it will not be: as the President of EFOST and as the Editor in Chief of MLTJ, I prompt you to keep it going. Please remember that all the abstracts of this congress are available, for free, on the MLTJ platform: please visit it, and contribute to the Journal.
An organization cannot survive without appropriate finances: many thanks, Jose, for having put in place the infrastructure for our safety and financial survival. I am sure that you will keep us right, and that you will reassure the membership that their dues are well spent.
We would not have been able to mount such a great congress without the help of our trade partners: to them, my thanks for the continuing support of EFOST.
We are now coming to the end of the WSTC – EFOST congress. GCO has helped us, and will continue to do so. Claudine, Simon: my thanks to you. In difficult personal circumstances, you have been close to EFOST, and you have believed in us. We look forward to continuing to work with you.
I look forward to continuing to work with the organisation of which I have been President, BOSTAA: the deep friendship that ties me to Roger, the ougoing president, and Mike, who will be president starting in a couple of hours, will make things easier.
This is an exciting time. Not just for me, as the new leader EFOST, but for all of you, for all of us. The opportunities are endless. I will work to ensure that, when my tenure is over and the new President will step into this role, he can see even farther down the tracks. The goal is to help usher the EFOST to a new place; not because we changed direction, but because we moved forward even faster.
Thank you again for this opportunity to serve you as president of EFOST. I appreciate your faith: I will do all I can to make these two years successful, enjoyable, and fun.
Nicola Maffulli
PMCID: PMC3671359
5.  Location of the Fracture Faces Within the Cell Envelope of Acinetobacter Species Strain MJT/F5/5 
Journal of Bacteriology  1974;118(2):693-707.
The cell wall of the gram-negative bacterium Acinetobacter species strain MJT/F5/5 shows in thin section an external “additional” layer, an outer membrane, an intermediate layer, and a dense layer. Negatively stained preparations showed that the additional layer is composed of hexagonally arranged subunits. In glycerol-treated preparations, freeze-etching revealed that the cell walls consist of four layers, with the main plane of fracture between layers cw 2 and cw 3. The surface of [Formula: see text] 2 consisted of densely packed particles, whereas [Formula: see text] 3 appeared to be fibrillar. In cell envelopes treated with lysozyme by various methods, the removal of the dense layer has detached the outer membrane and additional layer from the underlying layers, as shown in thin sections. When freeze-etched in the absence of glycerol, these detached outer membranes with additional layers fractured to reveal both the faces [Formula: see text] 2 and [Formula: see text] 3 with their characteristic surface structures, and, in addition, both the external and internal etched surfaces were revealed. This experiment provided conclusive evidence that the main fracture plane in the cell wall lies within the interior of the outer membrane. This and other evidence showed that the corresponding layers in thin sections and freeze-etched preparations are: the additional layer, cw 1; the outer membrane, cw (2 + 3); and the intermediate and dense layers together from cw 4. Because of similarities in structure between this Acinetobacter and other gram-negative bacteria, it seemed probable that the interior of the outer membrane is the plane most liable to fracture in the cell walls of most gram-negative bacteria.
PMCID: PMC246804  PMID: 4133353
6.  Scanning Strategies Do Not Modulate Face Identification: Eye-Tracking and Near-Infrared Spectroscopy Study 
PLoS ONE  2010;5(6):e11050.
During face identification in humans, facial information is sampled (seeing) and handled (processing) in ways that are influenced by the kind of facial image type, such as a self-image or an image of another face. However, the relationship between seeing and information processing is seldom considered. In this study, we aimed to reveal this relationship using simultaneous eye-tracking measurements and near-infrared spectroscopy (NIRS) in face identification tasks.
Methodology/Principal Findings
22 healthy adult subjects (8 males and 14 females) were shown facial morphing movies in which an initial facial image gradually changed into another facial image (that is, the subject's own face was changed to a familiar face). The fixation patterns on facial features were recorded, along with changes in oxyhemoglobin (oxyHb) levels in the frontal lobe, while the subjects identified several faces. In the self-face condition (self-face as the initial image), hemodynamic activity around the right inferior frontal gyrus (IFG) was significantly greater than in the familiar-face condition. On the other hand, the scanning strategy was similar in almost all conditions with more fixations on the eyes and nose than on other areas. Fixation time on the eye area did not correlate with changes in oxyHb levels, and none of the scanning strategy indices could estimate the hemodynamic changes.
We conclude that hemodynamic activity, i.e., the means of processing facial information, is not always modulated by the face-scanning strategy, i.e., the way of seeing, and that the right IFG plays important roles in both self-other facial discrimination and self-evaluation.
PMCID: PMC2883577  PMID: 20548791
7.  Quantification of late gadolinium enhanced CMR in viability assessment in chronic ischemic heart disease: a comparison to functional outcome 
Quantification of late gadolinium enhanced cardiovascular magnetic resonance (LGE CMR) by objective window setting increases reproducibility and facilitates multicenter comparison and cooperation. So far, quantification methods or models have only been validated to postmortem animal studies. This study was undertaken to evaluate quantification of LGE in relation to the clinical standard of viability, i.e. functional outcome after revascularization.
Thirty-eight patients with chronic ischemic myocardial dysfunction underwent cine and LGE 1 month before and cine CMR 6 months after coronary revascularization. Enhancement was quantified by thresholding window setting at: 2-8SD above mean signal intensity of a remote normal region, and according to the full width at half maximum method (FWHM). Dysfunctional segments were divided in 5 groups according to segmental extent of enhancement (SEE): SEE 1 – no enhancement to SEE 5 – 76–100% with each quantification method.
Quantification methods had a strong influence on SEE and total infarct size. Multilevel analysis showed that thresholding contrast images at 6SD best predicted segmental functional outcome after revascularization, but the difference with other methods was small and non-significant.
Simple thresholding techniques strongly influence global and segmental extent of LGE, but have relatively little influence on the accuracy to predict segmental functional improvement after revascularization.
PMCID: PMC2657135  PMID: 19272147
8.  Preparation of Adult Drosophila Eyes for Thin Sectioning and Microscopic Analysis 
Drosophila has long been used as model system to study development, mainly due to the ease with which it is genetically tractable. Over the years, a plethora of mutant strains and technical tricks have been developed to allow sophisticated questions to be asked and answered in a reasonable amount of time. Fundamental insight into the interplay of components of all known major signaling pathways has been obtained in forward and reverse genetic Drosophila studies. The fly eye has proven to be exceptionally well suited for mutational analysis, since, under laboratory conditions, flies can survive without functional eyes. Furthermore, the surface of the insect eye is composed of some 800 individual unit eyes (facets or ommatidia) that form a regular, smooth surface when looked at under a dissecting microscope. Thus, it is easy to see whether a mutation might affect eye development or growth by externally looking for the loss of the smooth surface ('rough eye' phenotype; Fig. 1) or overall eye size, respectively (for examples of screens based on external eye morphology see e.g.1). Subsequent detailed analyses of eye phenotypes require fixation, plastic embedding and thin-sectioning of adult eyes.
The Drosophila eye develops from the so-called eye imaginal disc, a bag of epithelial cells that proliferate and differentiate during larval and pupal stages (for review see e.g. 2). Each ommatidium consists of 20 cells, including eight photoreceptors (PR or R-cells; Fig. 2), four lens-secreting cone cells, pigment cells ('hexagon' around R-cell cluster) and a bristle. The photoreceptors of each ommatidium, most easily identified by their light sensitive organelles, the rhabdomeres, are organized in a trapezoid made up of the six "outer" (R1-6) and two "inner" photoreceptors (R7/8; R8 [Fig. 2] is underneath R7 and thus only seen in sections from deeper areas of the eye). The trapezoid of each facet is precisely aligned with those of its neighbors and the overall anteroposterior and dorsoventral axes of the eye (Fig. 3A). In particular, the ommatidia of the dorsal and ventral (black and red arrows, respectively) halves of the eye are mirror images of each other and correspond to two chiral forms established during planar cell polarity signaling (for review see e.g. 3).
The method to generate semi-thin eye sections (such as those presented in Fig. 3) described here is slightly modified from the one originally described by Tomlinson and Ready4. It allows the morphological analysis of all cells except for the transparent cone cells. In addition, the pigment of R-cells (blue arrowheads in Fig. 2 and 3) can be used as a cell-autonomous marker for the genotype of a R-cell, thus genetic requirements of genes in a subset of R-cells can readily be determined5,6.
PMCID: PMC3217632  PMID: 21897355
9.  Simplified method to perform CLARITY imaging 
Imaging methods are used widely to understand structure of brain and other biological objects. However, sample penetration by light microscopy is limited due to light scattering by the tissue. A number of methods have been recently developed to solve this problem. In one approach (SeeDB) simple procedure for clarifying brain samples for imaging was described. However, this method is not compatible with immunostaining approach as SeeDB-prepared tissue is not permeable to the antibodies. Another technique for clearing brain tissue (CLARITY) was optimized for immunochemistry, but this method technically much more demanding than SeeDB.
Here we report optimized protocol for imaging of brain samples (CLARITY2). We have simplified and shortened the original protocol. Following hydrogel fixation, we cut brain tissue to 1–1.5 mm thick coronal slices. This additional step enabled us to accelerate and simplify clearing, staining and imaging steps when compared to the original protocol. We validated the modified protocol in imaging experiments with brains from line M Thy1-GFP mouse and in immunostaining experiments with antibodies against postsynaptic protein PSD-95 and striatal-specific protein DARPP32.
The original CLARITY protocol was optimized and simplified. Application of the modified CLARITY2 protocol could be useful for a broad range of scientists working in neurobiology and developmental biology.
PMCID: PMC4049387  PMID: 24885504
CLARITY; See deep brain; Neuronal structure; 3D brain tissue reconstruction; Neuroimaging; Confocal; Two-photon
10.  Specific Image Characteristics Influence Attitudes about Chimpanzee Conservation and Use as Pets 
PLoS ONE  2011;6(7):e22050.
Chimpanzees are endangered in their native Africa but in the United States, they are housed not only in zoos and research centers but owned privately as pets and performers. In 2008, survey data revealed that the public is less likely to think that chimpanzees are endangered compared to other great apes, and that this is likely the result of media misportrayals in movies, television and advertisements. Here, we use an experimental survey paradigm with composite images of chimpanzees to determine the effects of specific image characteristics. We found that those viewing a photograph of a chimpanzee with a human standing nearby were 35.5% more likely to consider wild populations to be stable/healthy compared to those seeing the exact same picture without a human. Likewise, the presence of a human in the photograph increases the likelihood that they consider chimpanzees as appealing as a pet. We also found that respondents seeing images in which chimpanzees are shown in typically human settings (such as an office space) were more likely to perceive wild populations as being stable and healthy compared to those seeing chimpanzees in other contexts. These findings shed light on the way that media portrayals of chimpanzees influence public attitudes about this important and endangered species.
PMCID: PMC3135618  PMID: 21779372
11.  Abnormal Cortical Development after Premature Birth Shown by Altered Allometric Scaling of Brain Growth 
PLoS Medicine  2006;3(8):e265.
We postulated that during ontogenesis cortical surface area and cerebral volume are related by a scaling law whose exponent gives a quantitative measure of cortical development. We used this approach to investigate the hypothesis that premature termination of the intrauterine environment by preterm birth reduces cortical development in a dose-dependent manner, providing a neural substrate for functional impairment.
Methods and Findings
We analyzed 274 magnetic resonance images that recorded brain growth from 23 to 48 wk of gestation in 113 extremely preterm infants born at 22 to 29 wk of gestation, 63 of whom underwent neurodevelopmental assessment at a median age of 2 y. Cortical surface area was related to cerebral volume by a scaling law with an exponent of 1.29 (95% confidence interval, 1.25–1.33), which was proportional to later neurodevelopmental impairment. Increasing prematurity and male gender were associated with a lower scaling exponent (p < 0.0001) independent of intrauterine or postnatal somatic growth.
Human brain growth obeys an allometric scaling relation that is disrupted by preterm birth in a dose-dependent, sexually dimorphic fashion that directly parallels the incidence of neurodevelopmental impairments in preterm infants. This result focuses attention on brain growth and cortical development during the weeks following preterm delivery as a neural substrate for neurodevelopmental impairment after premature delivery.
Measurement of the way that the brain grows after birth in preterm infants, particularly the relation between surface area and cortical volume, may help to predict neurodevelopmental impairment.
Editors' Summary
Nowadays, many children who are born prematurely can be expected to survive. However, children who are born very prematurely have a high chance of having brain damage that leads to delayed development compared with children of the same age but who were not born prematurely. This delay continues into school age at least and is worse in boys than in girls. Although some children have large obvious areas of brain damage, shown on brain scans, most do not and the changes that cause the delay must be more subtle. One possibility is that the underlying abnormality may be due to the fact that in these children the surface of the brain grows at too slow a rate compared to the volume of the brain. It is already known that the human brain (and the brain of closely related monkeys) has a very high surface area compared to its volume and that during normal development this surface area grows much faster than the volume. This extra growth appears to be necessary for the brain to make all the connections it needs.
Why Was This Study Done?
The researchers wanted to look at how the different parts of the brain grew in very premature babies born before 30 weeks (the normal time of gestation is around 40 weeks). In particular, they wanted to see if there were changes in the rates at which the different parts of the brain grew in relation to each other (the study of the change in proportion of various parts of an organism as a consequence of growth is known as Allometrics—hence the title of the paper). They then wanted to see if the rates of brain growth were affected by a variety of factors, including the sex of the baby or how premature he or she was, and whether there was a relationship between the rate of brain growth and later delayed development.
What Did the Researchers Do and Find?
Using a specially designed magnetic resonance imaging (MRI) machine—a type of scanner that allows very detailed pictures to be taken of the brain—the authors took 274 images that recorded brain growth from 23 to 48 wk of gestation in 113 extremely premature infants born between 22 and 29 weeks of gestation. 63 of these children were then assessed to see how they were developing mentally at around 2 years of age. As expected, the researchers found that the brain surface area grew faster than the brain volume and that the rate of growth was proportional to the chances of having delayed development later—that is, the slower the rate of growth of surface area relative to volume the more likely there was to be delayed development. In addition, the more premature babies, and those that were male, were most likely to have a slower growth of the brain surface compared with the brain volume.
What Do These Findings Mean?
It seems that human brains grow during development in a particular way, which means that the surface area grows more than the volume. When babies are born prematurely this pattern of growth is disrupted, and the amount of disruption of the growth seems to predict whether there is delayed development 2 years later. The earlier the birth, the greater the disruption is; in addition, boys are affected more than girls. These results will need to be confirmed in more babies, but if they are correct then it may be possible to monitor brain growth after birth in order to predict which children might need development support later on. The research also suggests useful avenues for further work to understand the exact neuroanatomy of disability in these children.
Additional Information.
Please access these Web sites via the online version of this summary at
• MedlinePlus has a page of links to information on premature babies
• The March of Dimes is a US charity that funds research on prematurity
• Action Medical Research and Wellbeing are UK charities that fund research in this area
PMCID: PMC1523379  PMID: 16866579
12.  Two adjacent residues in staphylococcal enterotoxins A and E determine T cell receptor V beta specificity 
The T cell receptor (TCR) V beta-determining region of two bacterial superantigens, staphylococcal enterotoxin A (SEA) and SEE, has been mapped to the COOH-terminal region of SEA and SEE using a panel of recombinant SEA/SEE hybrids. Total TCR V beta mRNA enrichment in human peripheral blood T cell cultures was determined by a novel single-tube amplification technique using a redundant V beta-specific primer. SEA routinely enriched mRNA coding for hV beta 1.1, 5.3, 6.3, 6.4, 6.9, 7.3, 7.4, and 9.1, while SEE, which is 83% homologous to SEA, enriched hV beta 5.1, 6.3, 6.4, 6.9, and 8.1 mRNA. Exchanging residues 206 and 207 was sufficient to convert in toto the TCR V beta response of human peripheral T lymphocytes. In addition, an SEA-reactive murine T cell line, SO3 (mV beta 17), unresponsive to wild-type SEE responded to SEE- S206N207, while an SEE-specific human T cell line, Jurkat (hV beta 8.1), unresponsive to SEA was stimulated strongly by SEA-P206D207. Exchanging all other regions of SEA and SEE except residues 206 and 207 did little to change the V beta response. Thus, the V beta binding region appears to be a stable, discrete domain localized within the COOH-terminal region that is largely unaffected by the considerable amino acid variability between SEA and SEE. This region may interact directly with TCR V beta.
PMCID: PMC2190881  PMID: 8418198
13.  Ambulatory Visit Utilization in a National, Population-based Sample of Adults with Osteoarthritis 
Arthritis and rheumatism  2009;61(12):1694-1703.
To estimate the proportion of adults with osteoarthritis (OA) seeing various medical providers and ascertain factors affecting the likelihood of seeing an OA specialist.
We use data from the Medical Expenditures Panel Survey (MEPS), a stratified random sample of the civilian non-institutionalized population. We classify adults as having symptomatic OA if: (1) their medical conditions include at least one occurrence of ICD-9-CM 715, 716, or 719, and (2) they report joint pain, swelling, or stiffness during the previous twelve months. For the purpose of our analysis we define rheumatologists, orthopedists and physical therapists as OA specialists. We first estimate the proportion of OA individuals seen by OA specialists and other health care providers in a one-year period. We then use logistic regression to estimate the impact of demographic and clinical factors on the likelihood of seeing an OA specialist.
9,933 persons meet the definition of OA, representing 22.5 million adults in the U.S. Virtually all (92%) see physicians during the year; 34% see at least one OA specialist; 25% see an orthopedist, 11% a physical therapist, and 6% a rheumatologist. The following are significant positive predictors for seeing an OA specialist: higher educational attainment, having more comorbidities, and residing in the Northeastern U.S. Significant negative predictors for seeing OA specialists are being unmarried but previously married, and having no health insurance.
Most adults with OA do not visit OA specialists. Those without insurance and with lower levels of education are less likely to see these specialists.
PMCID: PMC2836231  PMID: 19950315
osteoarthritis; population studies
14.  Association of Non-alcoholic Fatty Liver Disease with Chronic Kidney Disease: A Systematic Review and Meta-analysis 
PLoS Medicine  2014;11(7):e1001680.
In a systematic review and meta-analysis, Giovanni Musso and colleagues examine the association between non-alcoholic fatty liver disease and chronic kidney disease.
Please see later in the article for the Editors' Summary
Chronic kidney disease (CKD) is a frequent, under-recognized condition and a risk factor for renal failure and cardiovascular disease. Increasing evidence connects non-alcoholic fatty liver disease (NAFLD) to CKD. We conducted a meta-analysis to determine whether the presence and severity of NAFLD are associated with the presence and severity of CKD.
Methods and Findings
English and non-English articles from international online databases from 1980 through January 31, 2014 were searched. Observational studies assessing NAFLD by histology, imaging, or biochemistry and defining CKD as either estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 or proteinuria were included. Two reviewers extracted studies independently and in duplicate. Individual participant data (IPD) were solicited from all selected studies. Studies providing IPD were combined with studies providing only aggregate data with the two-stage method. Main outcomes were pooled using random-effects models. Sensitivity and subgroup analyses were used to explore sources of heterogeneity and the effect of potential confounders. The influences of age, whole-body/abdominal obesity, homeostasis model of insulin resistance (HOMA-IR), and duration of follow-up on effect estimates were assessed by meta-regression. Thirty-three studies (63,902 participants, 16 population-based and 17 hospital-based, 20 cross-sectional, and 13 longitudinal) were included. For 20 studies (61% of included studies, 11 cross-sectional and nine longitudinal, 29,282 participants), we obtained IPD. NAFLD was associated with an increased risk of prevalent (odds ratio [OR] 2.12, 95% CI 1.69–2.66) and incident (hazard ratio [HR] 1.79, 95% CI 1.65–1.95) CKD. Non-alcoholic steatohepatitis (NASH) was associated with a higher prevalence (OR 2.53, 95% CI 1.58–4.05) and incidence (HR 2.12, 95% CI 1.42–3.17) of CKD than simple steatosis. Advanced fibrosis was associated with a higher prevalence (OR 5.20, 95% CI 3.14–8.61) and incidence (HR 3.29, 95% CI 2.30–4.71) of CKD than non-advanced fibrosis. In all analyses, the magnitude and direction of effects remained unaffected by diabetes status, after adjustment for other risk factors, and in other subgroup and meta-regression analyses. In cross-sectional and longitudinal studies, the severity of NAFLD was positively associated with CKD stages. Limitations of analysis are the relatively small size of studies utilizing liver histology and the suboptimal sensitivity of ultrasound and biochemistry for NAFLD detection in population-based studies.
The presence and severity of NAFLD are associated with an increased risk and severity of CKD.
Please see later in the article for the Editors' Summary
Editors' Summary
Chronic kidney disease (CKD)—the gradual loss of kidney function—is becoming increasingly common. In the US, for example, more than 10% of the adult population (about 26 million people) and more than 25% of individuals older than 65 years have CKD. Throughout life, the kidneys perform the essential task of filtering waste products (from the normal breakdown of tissues and from food) and excess water from the blood to make urine. CKD gradually destroys the kidneys' filtration units, the rate of blood filtration decreases, and dangerous amounts of waste products build up in the blood. Symptoms of CKD, which rarely occur until the disease is very advanced, include tiredness, swollen feet, and frequent urination, particularly at night. There is no cure for CKD, but progression of the disease can be slowed by controlling high blood pressure and diabetes (two risk factors for CKD), and by adopting a healthy lifestyle. The same interventions also reduce the chances of CKD developing in the first place.
Why Was This Study Done?
CKD is associated with an increased risk of end-stage renal (kidney) disease and of cardiovascular disease. These life-threatening complications are potentially preventable through early identification and treatment of CKD. Because early recognition of CKD has the potential to reduce its health-related burden, the search is on for new modifiable risk factors for CKD. One possible new risk factor is non-alcoholic fatty liver disease (NAFLD), which, like CKD is becoming increasingly common. Healthy livers contain little or no fat but, in the US, 30% of the general adult population and up to 70% of patients who are obese or have diabetes have some degree of NAFLD, which ranges in severity from simple fatty liver (steatosis), through non-alcoholic steatohepatitis (NASH), to NASH with fibrosis (scarring of the liver) and finally cirrhosis (extensive scarring). In this systematic review and meta-analysis, the researchers investigate whether NAFLD is a risk factor for CKD by looking for an association between the two conditions. A systematic review identifies all the research on a given topic using predefined criteria, meta-analysis uses statistical methods to combine the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 33 studies that assessed NAFLD and CKD in nearly 64,000 participants, including 20 cross-sectional studies in which participants were assessed for NAFLD and CKD at a single time point and 13 longitudinal studies in which participants were assessed for NAFLD and then followed up to see whether they subsequently developed CKD. Meta-analysis of the data from the cross-sectional studies indicated that NAFLD was associated with a 2-fold increased risk of prevalent (pre-existing) CKD (an odds ratio [OR]of 2.12; an OR indicates the chance that an outcome will occur given a particular exposure, compared to the chance of the outcome occurring in the absence of that exposure). Meta-analysis of data from the longitudinal studies indicated that NAFLD was associated with a nearly 2-fold increased risk of incident (new) CKD (a hazard ratio [HR] of 1.79; an HR indicates often a particular event happens in one group compared to how often it happens in another group, over time). NASH was associated with a higher prevalence and incidence of CKD than simple steatosis. Similarly, advanced fibrosis was associated with a higher prevalence and incidence of CKD than non-advanced fibrosis.
What Do These Findings Mean?
These findings suggest that NAFLD is associated with an increased prevalence and incidence of CKD and that increased severity of liver disease is associated with an increased risk and severity of CKD. Because these associations persist after allowing for established risk factors for CKD, these findings identify NAFLD as an independent CKD risk factor. Certain aspects of the studies included in this meta-analysis (for example, only a few studies used biopsies to diagnose NAFLD; most used less sensitive tests that may have misclassified some individuals with NAFLD as normal) and the methods used in the meta-analysis may limit the accuracy of these findings. Nevertheless, these findings suggest that individuals with NAFLD should be screened for CKD even in the absence of other risk factors for the disease, and that better treatment of NAFLD may help to prevent CKD.
Additional Information
Please access these websites via the online version of this summary at
The US National Kidney and Urologic Diseases Information Clearinghouse provides information about all aspects of kidney disease; the US National Digestive Diseases Information Clearinghouse provides information about non-alcoholic liver disease
The US National Kidney Disease Education Program provides resources to help improve the understanding, detection, and management of kidney disease (in English and Spanish)
The UK National Health Service Choices website provides information for patients on chronic kidney disease, including some personal stories, and information on non-alcoholic fatty liver disease
The US National Kidney Foundation, a not-for-profit organization, provides information about chronic kidney disease (in English and Spanish)
The not-for-profit UK National Kidney Federation provides support and information for patients with kidney disease and for their carers
The British Liver Trust, a not-for-profit organization, provides information about non-alcoholic fatty liver disease, including a patient story
PMCID: PMC4106719  PMID: 25050550
15.  Temporal structure in associative retrieval 
eLife  null;4:e04919.
Electrophysiological data disclose rich dynamics in patterns of neural activity evoked by sensory objects. Retrieving objects from memory reinstates components of this activity. In humans, the temporal structure of this retrieved activity remains largely unexplored, and here we address this gap using the spatiotemporal precision of magnetoencephalography (MEG). In a sensory preconditioning paradigm, 'indirect' objects were paired with 'direct' objects to form associative links, and the latter were then paired with rewards. Using multivariate analysis methods we examined the short-time evolution of neural representations of indirect objects retrieved during reward-learning about direct objects. We found two components of the evoked representation of the indirect stimulus, 200 ms apart. The strength of retrieval of one, but not the other, representational component correlated with generalization of reward learning from direct to indirect stimuli. We suggest the temporal structure within retrieved neural representations may be key to their function.
eLife digest
Seeing an object triggers a complex and carefully orchestrated dance of brain activity. The spatial pattern of the brain activity encoding the object can change multiple times even within the first second of seeing the object. These rapid changes appear to be a core feature of how the brain understands and processes objects.
Yet little is known about how these patterns unfold through time when we remember an object. Remembering, or retrieving information about objects, is how we use our knowledge of the world to make good decisions. It is not clear whether, during remembering, there are rapid changes in the patterns similar to those that happen when directly seeing an object. Mapping brain activity during remembering could help us understand how stored information can guide decisions.
Using recently developed methods in brain imaging and statistics, Kurth-Nelson et al. found that two distinct patterns of brain activity appeared when viewing particular objects. One occurred around 200 milliseconds after viewing an object, and the other appeared a bit later, by about 400 milliseconds. Later, when remembering the object, these patterns reappeared in the brain, but at different points in time. Furthermore, these two patterns had distinct roles in learning associated with the objects to guide later decisions.
This work shows that rapid changes in the pattern of neuronal activity are central to how stored information is retrieved and used to make decisions.
PMCID: PMC4303761  PMID: 25615722
representation; MEG; multivariate; memory; retrieval; model; Human
16.  Object-based auditory facilitation of visual search for pictures and words with frequent and rare targets 
Acta psychologica  2010;137(2):252-259.
Auditory and visual processes demonstrably enhance each other based on spatial and temporal coincidence. Our recent results on visual search have shown that auditory signals also enhance visual salience of specific objects based on multimodal experience. For example, we tend to see an object (e.g., a cat) and simultaneously hear its characteristic sound (e.g., “meow”), to name an object when we see it, and to vocalize a word when we read it, but we do not tend to see a word (e.g., cat) and simultaneously hear the characteristic sound (e.g., “meow”) of the named object. If auditory-visual enhancements occur based on this pattern of experiential associations, playing a characteristic sound (e.g., “meow”) should facilitate visual search for the corresponding object (e.g., an image of a cat), hearing a name should facilitate visual search for both the corresponding object and corresponding word, but playing a characteristic sound should not facilitate visual search for the name of the corresponding object. Our present and prior results together confirmed these experiential-association predictions. We also recently showed that the underlying object-based auditory-visual interactions occur rapidly (within 220 ms) and guide initial saccades towards target objects. If object-based auditory-visual enhancements are automatic and persistent, an interesting application would be to use characteristic sounds to facilitate visual search when targets are rare, such as during baggage screening. Our participants searched for a gun among other objects when a gun was presented on only 10% of the trials. The search time was speeded when a gun sound was played on every trial (primarily on gun-absent trials); importantly, playing gun sounds facilitated both gun-present and gun-absent responses, suggesting that object-based auditory-visual enhancements persistently increase the detectability of guns rather than simply biasing gun-present responses. Thus, object-based auditory-visual interactions that derive from experiential associations rapidly and persistently increase visual salience of corresponding objects.
PMCID: PMC3010345  PMID: 20864070
17.  Spatial localization accuracy of radiologists in free-response studies: inferring perceptual FROC curves from mark-rating data 
Academic radiology  2007;14(1):4-18.
Free-response data consists of a set of mark-ratings pairs. Prior to analysis the data is classified or “scored” into lesion and non-lesion localizations. The scoring is done by choosing an acceptance-radius and classifying marks within the acceptance-radius of lesion centers as lesion localizations, and all other marks are classified as non-lesion localizations. The scored data is plotted as a free-response receiver operating characteristic (FROC) curve, essentially a plot of appropriately normalized numbers of lesion localizations vs. non-lesion localizations. Scored FROC curves are frequently used to compare imaging systems and computer aided detection (CAD) algorithms. However, the choice of acceptance-radius is arbitrary. This makes it difficult to compare curves from different studies and to estimate true performance. To resolve this issue the concept of two types of marks is introduced: perceptual hits and perceptual misses. A perceptual hit is a mark made in response to the observer seeing the lesion. A perceptual miss is a mark made in response to the observer seeing a (lesion-like) non-lesion. A method of estimating the most probable numbers of perceptual hits and misses is described. This allows one to plot a perceptual FROC operating point and by extension a perceptual FROC curve. Unlike a scored FROC operating point, a perceptual point is independent of the choice of acceptance-radius. The method does not allow one to identify individual marks as perceptual hits or misses – only the most probable numbers. It is based on a 3-parameter statistical model of the spatial distributions of perceptual hits and misses relative to lesion centers. The method has been applied to an observer dataset in which mammographers, and residents with different levels of experience were asked to locate lesions in mammograms. The perceptual operating points suggest superior performance for the mammographers and equivalent performance for residents in the first and second mammography rotations. These results and the model validation are preliminary as they are based on a small dataset. The significance of this study is showing that it is possible to probabilistically determine if a mark resulted from seeing a lesion or a nonlesion. Using the method developed in this study one could perform acceptance- radius independent estimation of observer performance.
PMCID: PMC1829298  PMID: 17178361
localization accuracy; FROC curves; acceptance-radius; observer performance; perceptual analysis; imaging systems assessment; CAD evaluation
18.  Effects of Body-Color Mutations on Vitality: An Attempt to Establish Easy-to-Breed See-Through Medaka Strains by Outcrossing 
G3: Genes|Genomes|Genetics  2013;3(9):1577-1585.
“See-through” strains of medaka are unique tools for experiments: their skin is transparent, and their internal organs can be externally monitored throughout life. However, see-through fish are less vital than normally pigmented wild-type fish, which allows only skilled researchers to make the most of their advantages. Expecting that hybrid vigor (heterosis) would increase the vitality, we outcrossed two see-through strains (SK2 and STIII) with a genetically distant wild-type strain (HNI). Fish with the see-through phenotypes were successfully restored in the F2 generation and maintained as closed colonies. We verified that genomes of these hybrid see-through strains actually consisted of approximately 50% HNI and approximately 50% SK2 or STIII alleles, but we could not obtain evidence supporting improved survival of larvae or fecundity of adults, at least under our breeding conditions. We also found that four of the five see-through mutations (bg8, i-3, gu, and il-1 but not lf) additively decrease viability. Given that heterosis could not overwhelm the viability-reducing effects of the see-through mutations, easy-to-breed see-through strains will only be established by other methods such as conditional gene targeting or screening of new body-color mutations that do not reduce viability.
PMCID: PMC3755918  PMID: 23893740
medaka; oculocutaneous albinism type 2 (oca2); solute carrier family 45 member 2 (slc45a2); leucophore free; guanineless; iridophoreless-1
19.  To see or not to see: a qualitative interview study of patients’ views on their own diagnostic images 
BMJ Open  2014;4(7):e004999.
To ascertain what meaning individuals attach to perceiving images of their own interior body and how the images and their meanings affect the clinical consultation.
Face-to-face semistructured interviews.
25 adult patients in southern England who, within the preceding 12 months, had been referred for diagnostic imaging.
For patients, being shown their own X-rays, MRIs or CT images creates a variety of effects: (1) a sense of better understanding of the diagnosis; (2) validation of their sensory and emotional response to the illness or injury and (3) an alteration to the tenor and nature of the clinical encounter between patient and physician. In addition to meanings attached to these images, patients also impute meaning to the physician's decision not to share an image with them. The desire to see their image was greater in those patients with a skeletal injury; patients are less keen on viewing abdominal or other soft tissue images.
Viewing images of one's interior, invisible body is powerful and resonant in a number of ways. The experience of not seeing, whether through the patient's or the physician's choice, is also fraught with meaning.
PMCID: PMC4120403  PMID: 25082418
Primary Care; Qualitative Research
20.  Stimulus Requirements for Face Perception: An Analysis Based on “Totem Poles” 
The stimulus requirements for perceiving a face are not well defined but are presumably simple, for vivid faces can often by seen in random or natural images such as cloud or rock formations. To characterize these requirements, we measured where observers reported the impression of faces in images defined by symmetric 1/f noise. This allowed us to examine the prominence and properties of different features and their necessary configurations. In these stimuli many faces can be perceived along the vertical midline, and appear stacked at multiple scales, reminiscent of “totem poles.” In addition to symmetry, the faces in noise are invariably upright and thus reveal the inversion effects that are thought to be a defining property of configural face processing. To a large extent, seeing a face required seeing eyes, and these were largely restricted to dark regions in the images. Other features were more subordinate and showed relatively little bias in polarity. Moreover, the prominence of eyes depended primarily on their luminance contrast and showed little influence of chromatic contrast. Notably, most faces were rated as clearly defined with highly distinctive attributes, suggesting that once an image area is coded as a face it is perceptually completed consistent with this interpretation. This suggests that the requisite trigger features are sufficient to holistically “capture” the surrounding noise structure to form the facial representation. Yet despite these well articulated percepts, we show in further experiments that while a pair of dark spots added to noise images appears face-like, these impressions fail to elicit other signatures of face processing, and in particular, fail to elicit an N170 or fixation patterns typical for images of actual faces. These results suggest that very simple stimulus configurations are sufficient to invoke many aspects of holistic and configural face perception while nevertheless failing to fully engage the neural machinery of face coding, implying that that different signatures of face processing may have different stimulus requirements.
PMCID: PMC3569666  PMID: 23407599
face perception; face detection; configural coding; facial features; symmetry; inversion effects; noise
21.  Fracture Faces in the Cell Envelope of Escherichia coli 
Journal of Bacteriology  1971;108(1):474-481.
Freeze-fracturing of Escherichia coli cells in the presence of 30% (v/v) glycerol resulted in a double cleavage of the cell envelope exposing two convex and two concave fracture faces ([Formula: see text], [Formula: see text] and [Formula: see text], [Formula: see text]) with characteristic patterns. Complementary replicas revealed the relationship of the fracture faces to their corresponding fracture planes. The inner fracture plane splits the plasma membrane at one particular level. Apparently the outer fracture plane was located in the outer part of the wall, as it was separated by a layer ([Formula: see text]) from the fractured profile (CW1) presumably corresponding to the murein layer. The outer fracture plane did alternate toward the cell periphery, exposing complementary smooth areas ([Formula: see text] and [Formula: see text]). When cells were freeze-fractured in the absence of glycerol, the outer cell surface appeared as an etching face rather than a fracture face. A schematic representation of the relative location of the different fracture faces in the E. coli cell envelope is given.
PMCID: PMC247088  PMID: 4941567
22.  Depth-resolved Optical Imaging and Microscopy of Vascular Compartment Dynamics During Somatosensory Stimulation 
NeuroImage  2007;35(1):89-104.
The cortical hemodynamic response to somatosensory stimulus is investigated at the level of individual vascular compartments using both depth-resolved optical imaging and in-vivo two-photon microscopy. We utilize a new imaging and spatiotemporal analysis approach that exploits the different characteristic dynamics of responding arteries, arterioles, capillaries and veins to isolate their three-dimensional spatial extent within the cortex. This spatial delineation is validated using vascular casts. Temporal delineation is supported by in-vivo two-photon microscopy of the temporal dynamics and vascular mechanisms of the arteriolar and venous responses.
Using these techniques we have been able to characterize the roles of the different vascular compartments in generating and controlling the hemodynamic response to somatosensory stimulus. We find that changes in arteriolar total hemoglobin concentration agree well with arteriolar dilation dynamics, which in turn correspond closely with changes in venous blood flow. For four-second stimuli, we see only small changes in venous hemoglobin concentration, and do not detect measurable dilation or ballooning in the veins. Instead, we see significant evidence of capillary hyperemia.
We compare our findings to historical observations of the composite hemodynamic response from other modalities including functional magnetic resonance imaging. Implications of our results are discussed with respect to mathematical models of cortical hemodynamics, and to current theories on the mechanisms underlying neurovascular coupling. We also conclude that our spatiotemporal analysis approach is capable of isolating and localizing signals from the capillary bed local to neuronal activation, and holds promise for improving the specificity of other hemodynamic imaging modalities.
PMCID: PMC1994243  PMID: 17222567
23.  Cross-Modal Multivariate Pattern Analysis 
Multivariate pattern analysis (MVPA) is an increasingly popular method of analyzing functional magnetic resonance imaging (fMRI) data1-4. Typically, the method is used to identify a subject's perceptual experience from neural activity in certain regions of the brain. For instance, it has been employed to predict the orientation of visual gratings a subject perceives from activity in early visual cortices5 or, analogously, the content of speech from activity in early auditory cortices6.
Here, we present an extension of the classical MVPA paradigm, according to which perceptual stimuli are not predicted within, but across sensory systems. Specifically, the method we describe addresses the question of whether stimuli that evoke memory associations in modalities other than the one through which they are presented induce content-specific activity patterns in the sensory cortices of those other modalities. For instance, seeing a muted video clip of a glass vase shattering on the ground automatically triggers in most observers an auditory image of the associated sound; is the experience of this image in the "mind's ear" correlated with a specific neural activity pattern in early auditory cortices? Furthermore, is this activity pattern distinct from the pattern that could be observed if the subject were, instead, watching a video clip of a howling dog?
In two previous studies7,8, we were able to predict sound- and touch-implying video clips based on neural activity in early auditory and somatosensory cortices, respectively. Our results are in line with a neuroarchitectural framework proposed by Damasio9,10, according to which the experience of mental images that are based on memories - such as hearing the shattering sound of a vase in the "mind's ear" upon seeing the corresponding video clip - is supported by the re-construction of content-specific neural activity patterns in early sensory cortices.
PMCID: PMC3308596  PMID: 22105246
24.  Predicting AH1N1 2009 influenza epidemic in Southeast Europe 
Croatian Medical Journal  2011;52(2):115-125.
To use the data on the AH1N1 2009 influenza epidemic in the Southern hemisphere countries to predict the course and size of the upcoming influenza epidemic in South-Eastern Europe (SEE) countries and other regions of the World with temperate climate.
We used a comparative epidemiological method to evaluate accessible electronic data on laboratory-confirmed deaths from AH1N1 2009 influenza in the seasons 2009/2010 and 2010/2011. The studied SEE countries were Albania, Bosnia and Herzegovina, Bulgaria, Croatia, Greece, Hungary, Kosovo, Macedonia, Montenegro, Romania, Serbia, and Slovenia, while Southern hemisphere countries were Argentina, Australia, Chile, New Zealand, Paraguay, Uruguay, and South Africa.
In influenza season 2009/2010, Southern hemisphere countries with temperate climate reported 1187 laboratory-confirmed influenza AH1N1 2009 deaths (mortality rate 0.84/100 000; 95% confidence interval [CI], 0.50-1.24). SEE countries with similar climatic conditions reported 659 deaths and similar mortality rates (0.86/100 000, 95% CI, 0.83-1.10). In the whole Europe without the Commonwealth of Independent States countries (CIS, former Soviet Union), there were 3213 deaths (0.60/100 000; 95% CI, 0.65-0.93). In 2010/2011, Southern hemisphere countries reported 94 laboratory-confirmed deaths (mortality rate 0.07/100 000; 95% CI, 0.02-0.28) or only 7.9% of the previous season. SEE countries by the end of the 11th epidemiological week of 2010/2011 season reported 489 laboratory-confirmed deaths, with a mortality rate of 0.64/100 000 (95% CI, 0.26-0.96) or 74.2% of the previous season, which was significantly higher than in the Southern hemisphere countries (χ21 = 609.1, P < 0.001). In Europe without CIS countries, there were 1836 deaths, with a mortality rate of 0.34/100 000 (χ2 = 153.3, P < 0.001 vs SEE countries).
In the 2009/2010 season, SEE countries and Southern hemisphere countries had similar influenza AH1N1 2009 mortality rates. In the 2010/2011 season, the forecast of 10% increase in total mortality in SEE countries and Europe compared with the 2009/2010 season was significantly exceeded, while the expected impact of type-specific vaccines against influenza AH1N1 2009 was not achieved. Consumption of epidemic potential has greater importance for the prognosis of the course and size of influenza epidemic than the degree of vaccine immunity.
PMCID: PMC3081209  PMID: 21495193
25.  Live Imaging of Innate Immune Cell Sensing of Transformed Cells in Zebrafish Larvae: Parallels between Tumor Initiation and Wound Inflammation 
PLoS Biology  2010;8(12):e1000562.
Live imaging and genetic studies of the initial interactions between leukocytes and transformed cells in zebrafish larvae indicate an attractant role for H2O2 and suggest that blocking these early interactions reduces expansion of transformed cell clones.
It has not previously been possible to live image the earliest interactions between the host environment and oncogene-transformed cells as they initiate formation of cancers within an organism. Here we take advantage of the translucency of zebrafish larvae to observe the host innate immune cell response as oncogene-transformed melanoblasts and goblet cells multiply within the larval skin. Our studies indicate activation of leukocytes at very early stages in larvae carrying a transformed cell burden. Locally, we see recruitment of neutrophils and macrophages by 48 h post-fertilization, when transformed cells are still only singletons or doublets, and soon after this we see intimate associations between immune and transformed cells and frequent examples of cytoplasmic tethers linking the two cell types, as well as engulfment of transformed cells by both neutrophils and macrophages. We show that a major component of the signal drawing inflammatory cells to oncogenic HRASG12V-transformed cells is H2O2, which is also a key damage cue responsible for recruiting neutrophils to a wound. Our short-term blocking experiments show that preventing recruitment of immune cells at these early stages results in reduced growth of transformed cell clones and suggests that immune cells may provide a source of trophic support to the transformed cells just as they do at a site of tissue repair. These parallels between the inflammatory responses to transformed cells and to wounds reinforce the suggestion by others that cancers resemble non-healing wounds.
Author Summary
The translucency of zebrafish larvae allows us to live image the earliest dynamic interactions between host innate immune cells and oncogene-transformed cell clones as they first establish themselves as the precursors of full-blown cancer. These early associations manifest via cytoplasmic tethers between an immune cell and a transformed cell, and occasional phagocytic engulfment. Immune cells are first attracted to transformed cells at surprisingly early stages, before transformed cells have had a chance to form clones and are thus still singletons or doublets. We show that the key attractant is hydrogen peroxide (H2O2), which was also recently shown to be the essential early damage signal responsible for drawing neutrophils to wounds. Tissue transplantation experiments allow us to test which cells are responsible for generating the H2O2 attractant, and we show that both transformed cells and their otherwise healthy neighbors contribute. Blocking H2O2 synthesis, either pharmacologically or by morpholino-mediated knockdown of DUOX, the enzyme responsible for H2O2 synthesis in larval skin, very significantly reduces the numbers of neutrophils and macrophages drawn to transformed cell clones, and this results in reduced numbers of transformed cells, suggesting that innate immune cells play a trophic and/or support role in early transformed cell growth.
PMCID: PMC3001901  PMID: 21179501

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