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Photodynamic therapy (PDT) is a non-to-minimally invasive treatment modality that utilizes photoactivatable drugs called photosensitizers to disrupt tumors with locally photoproduced reactive oxygen species (ROS). Photosensitizer activation by light results in hyperoxidative stress and subsequent tumor cell death, vascular shutdown and hypoxia, and an antitumor immune response. However, sublethally afflicted tumor cells initiate several survival mechanisms that account for decreased PDT efficacy. The hypoxia inducible factor 1 (HIF-1) pathway is one of the most effective cell survival pathways that contributes to cell recovery from PDT-induced damage. Several hundred target genes of the HIF-1 heterodimeric complex collectively mediate processes that are involved in tumor cell survival directly and indirectly (e.g., vascularization, glucose metabolism, proliferation, and metastasis). The broad spectrum of biological ramifications culminating from the activation of HIF-1 target genes reflects the importance of HIF-1 in the context of therapeutic recalcitrance. This chapter elaborates on the involvement of HIF-1 in cancer biology, the hypoxic response mechanisms, and the role of HIF-1 in PDT. An overview of inhibitors that either directly or indirectly impede HIF-1-mediated survival signaling is provided. The inhibitors may be used as pharmacological adjuvants in combination with PDT to augment therapeutic efficacy.

Contains fulltext : 226717.pdf (Publisher’s version ) (Closed access) Despite an ongoing stream of lamentations, many empirical disciplines still treat the p value as the sole arbiter to separate the scientific wheat from the chaff. The continued reign of the p value is arguably due in part to a perceived lack of workable alternatives. In order to be workable, any alternative methodology must be (1) relevant: it has to address the practitioners' research question, which - for better or for worse- most often concerns the test of a hypothesis, and less often concerns the estimation of a parameter; (2) available: it must have a concrete implementation for practitioners' statistical workhorses such as the t test, regression, and ANOVA; and (3) easy to use: methods that demand practitioners switch to the theoreticians' programming tools will face an uphill struggle for adoption. The above desiderata are fulfilled by Harold Jeffreys's Bayes factor methodology as implemented in the open-source software JASP. We explain Jeffreys's methodology and showcase its practical relevance with two examples. 9 p.

List of contributors Preface: Maarten Bouman and the limits of perception List of publications by M.A. Bouman List of doctoral dissertations supervised by M.A. Bouman PART 1: A PHYSICIST'S APPROACH TO THE LIMITS IN PERCEPTION Development and present status of the quantum concept in visual psychophysics Peter Zuidema The physical constraints of color vision Johannes J. Vos and Pieter L. Walraven Limits of the visual spectrum Johannes J. Vos and Dirk van Norren Limits of the eye-optics Aart van Meeteren and Johannes J. Vos PART 2: AN ENGINEER'S APPROACH TO THE LIMITS IN PERCEPTION The modulation transfer function in audition Reinier Plomp, Tammo Houtgast and Herman J.M. Steeneken Interchangeability of space and time in perception Gerjan van der Wildt Perceptual limits in man-machine communication Floris L. van Nes PART 3: PSYCHOPHYSICAL APPROACHES TO THE LIMITS IN PERCEPTION Limits in spatio-temporal correlation and the perception of visual movement Andrea J. van Doorn, Jan J. Koenderink and Wim A. van de Grind Limits in vision with two eyes Charles M.M. de Weert On the hierarchy of sensory processes Gert van den Brink PART 4: PSYCHOLOGICAL APPROACHES TO THE LIMITS IN PERCEPTION Some perceptual limitations on talking about space Willem J.M. Levelt The functional visual field revisited Andries F. Sanders and Tilly J.M. Houtmans Concatenation of short time intervals John A. Michon, Annie Bruinsma and Wim J. Riedel PART 5: THEORETICAL APPROACHES TO THE LIMITS IN PERCEPTION Visual adaptation and response saturation Jan Walravan and J. MathA(c) Valeton Decomposition and neuroreduction of visual perception Wim A. van de Grind The concept of local sign Jan J. Koenderink Subject index

Against a background of the pluralisation of policing in contemporary city spaces, and sustained interests in the assessment of policing in the criminology and criminal justice literatures, the current study seeks to draw a comparative analysis in trust between policing actors, as experienced by nightlife consumers. While studies on trust in the police are numerous, this is much less the case for other actors involved in policing urban (nightlife) spaces. Neither is it very well understood how trust is distributed between policing actors. It is important to investigate this, taking into consideration the privatisation and technologisation of safety provision in contemporary cities, and the legitimacy of the actors involved. Using a survey, 894 youths enrolled in education were asked to evaluate their trust in actors involved in the policing of urban nightlife areas: the police, door staff, and CCTV. Results showed that people tend to trust human policing agents more compared to technological agents. A cluster analysis further indicated that alongside this general pattern, four additional groups can be found in the data: two groups that display the highest trust in either the police or door staff with intermediate trust in CCTV, and two groups expressing either overall low trust or overall high trust, independent of the policing actor. Employing logistic regression analyses, we find that demographic, victimisation, and contextual variables predict cluster membership. We end with suggestions for future research and reflect on whether the privatisation and technologisation of (nightlife) policing are desirable from a nightlife consumer point of view.

People are often confronted with injustice that is done to others. In such cases, observers (i.e. third-parties) of injustice can restore justice by punishing the perpetrator, as shown by a vast amount of research. However, this focus on punishment has led to the neglect of another behavioural option: compensation of the victim. The current review focuses on this latter behavioural option. More specifically, it is argued that third-parties are more compensation-oriented than previous literature appears to demonstrate. To support this argument, previous research is discussed and the factors that might explain observers’ preference for compensation are outlined. To conclude, suggestions for future research are presented.

Shading is a visual artist’s tool. It enables the indication of ‘landmarks’ inside the outline of shapes. Shading triggers behavioral responses in organisms throughout the animal kingdom and even affects the habitus of plants. Radiometry might be expected to account for the phenomenology. We derive the formal structures of shading that are expected to play a dominant role in perception. That they fail to do so suggests that shading is more of an interface template than a ‘cue’. This fits the artistic use as a ‘releaser’ very well. Pre-modern artists hardly acknowledge causal relations between various photometric variables. Their works show an effective use of various elements in their own right, without attempts at causal congruity. Modern art often defies physics on purpose. We identify manifest templates and relate these to conventional techniques in the visual arts.

Nous abordons ici l’etude de la phenomenologie des objets visuels a partir de comptes rendus verbaux, de reponses a des questions ou de descriptions spontanees, ainsi que d’associations libres. Nous demandons meme parfois aux sujets de realiser de simples croquis. Cet eventail de methodes permet de sonder la structure profonde de la conscience visuelle. Celle-ci est avant tout revelee par ce qui n’est pas spontanement mentionne par des qualites accidentelles ou encore par des changements induits lors de variations ou ajouts mineurs. Nous avons trouve une concordance remarquable parmi un grand nombre de participants. Ceci demonte que les comptes-rendus verbaux permettent d’explorer puissamment la structure de la conscience visuelle. Tout comme le langage, les « objets visuels simples » ont des racines profondes dans la conscience. Ces fondations « invisibles » servent a definir des figures simples, un « carre » par exemple, comme des objets prototypiques et uniques. La nature des « objets visuels » implique ainsi l’existence d’un « vaste domaine invisible ». Sans une telle prise en compte, la comprehension correcte de la nature de l’objet visuel n’est pas possible. Cette decouverte devrait permettre de mener a une theorie de la syntaxe formelle des formes visuelles fondamentales.

A high radiographic inclination angle (RI) contributes to accelerated wear and has been associated with dislocation after total hip arthroplasty (THA). With freehand positioning of the acetabular component there is a lack of accuracy, with a trend towards a high radiographic inclination angle. The aim of this study was to investigate whether the use of a digital protractor to measure the operative inclination angle (OI) could improve the positioning of the acetabular component in relation to a ‘safe zone’.We measured the radiographic inclination angles of 200 consecutive uncemented primary THAs. In the first 100 the component was introduced freehand and in the second 100 a digital protractor was used to measure the operative inclination angle.The mean difference between the operative and the radiographic inclination angles (∆RI–OI) in the second cohort was 12.3° (3.8° to 19.8°). There was a strong correlation between the circumference of the hip and ∆RI–OI. The number of RI outliers was significantly reduced in the protractor group (p = 0.002).Adjusting the OI, using a digital protractor and taking into account the circumference of the patient’s hip, improves the RI significantly (p < 0.001) and does not require additional operating time.Cite this article: Bone Joint J 2015; 97-B:603–610.

We consider techniques used in the articulation of pictorial relief. The related ‘cue’ best known to vision science is ‘shading’. It is discussed in terms of an inverse optics algorithm known as ‘shape from shading’. However, the familiar techniques of the visual arts count many alternative cues for the articulation of pictorial relief. From an art technical perspective these cues are well known. Although serving a similar purpose as shading proper, they allow a much flatter value scale, making it easier to retain the picture plane, or major tonal areas. Vision research has generally ignored such methods, possibly because they lack an obvious basis in ecological optics. We attempt to rate the power of various techniques on a common ‘shading scale’. We find that naive observers spontaneously use a variety of cues, and that several of these easily equal, or beat, conventional shading. This is of some conceptual interest to vision science, because shading has a generally acknowledged ecological basis, whereas the alternative methods lack this.

Objective and design Non-islet cell tumour induced hypoglycaemia (NICTH) is a paraneoplastic phenomenon that is associated with the formation of several isoforms of pro-insulin like growth factor 2 (pro-IGF-II), or so called “big” IGF-II. Disturbance of ternary complex formation by big IGF-II is assumed to be a crucial early event in the pathogenic cascade of hypoglycaemia. By size-exclusion chromatography, we investigated complex formation by adding different naturally occurring isoforms of pro-IGF-II to pooled normal adult serum. Results were compared with the analysis of the serum from a patient with NICTH. Results Gel filtration experiments with the serum of a patient with NICTH demonstrated that ternary complex formation was severely compromised. The various forms of pro-IGF-II did not induce a shift of IGF-binding protein 3 (IGFBP-3) from 150 kD towards smaller binary complexes in the normal adult serum, suggesting that they did not interfere with the interaction between the acid labile subunit and IGFBP-3. Instead, unglycosylated recombinant pro-IGF-II[1–104] was capable of forming a 150 kD complex. In contrast, predominantly glycosylated and unglycosylated pro-IGF-II[1–87] eluted in the free unbound form. We showed that mature IGF-II and isoforms of pro-IGF-II were able to phosphorylate the IGF-I receptors of MC7 cells, albeit to a markedly lesser extent than IGF-I. When the patient's serum was tested in this system, the IGF-I receptor phosphorylation activity was considerably less than that in sera from age matched healthy individuals. Conclusion We postulate that, alongside the presence of big IGF-II in the circulation, additional steps are required to stimulate the release of IGF-II and pro-IGF-II isoforms from IGFBPs in vivo. These factors may be proteases, that are present in the local environment of the tumour and in insulin-sensitive tissues.

The orientation of the acetabular component can influence both the short- and long-term outcomes of total hip replacement (THR). We performed a prospective, randomised, controlled trial of two groups, comprising of 40 patients each, in order to compare freehand introduction of the component with introduction using the transverse acetabular ligament (TAL) as a reference for anteversion. Anteversion and inclination were measured on pelvic radiographs.With respect to anteversion, in the freehand group 22.5% of the components were outside the safe zone versus 0% in the transverse acetabular ligament group (p = 0.002). The mean angle of anteversion in the freehand group was 21° (2° to 35°) which was significantly higher compared with 17° (2° to 25°) in the TAL group (p = 0.004). There was a significant difference comparing the variations of both groups (p = 0.008).With respect to inclination, in the freehand group 37.5% of the components were outside the safe zone versus 20% in the TAL group (p = 0.14). There was no significant difference regarding the accuracy or variation of the angle of inclination when comparing the two groups.The transverse acetabular ligament may be used to obtain the appropriate anteversion when introducing the acetabular component during THR, but not acetabular component inclination.Cite this article: Bone Joint J 2014;96-B:312–18.

To investigate the effect of caudal zona incerta-deep brain stimulation (cZi-DBS) on word-level speech intelligibility in patients with Parkinson's disease, under both an optimal listening condition and a simulated more naturalistic listening condition.Spoken single words were extracted from read samples collected from 10 bilaterally implanted patients with PD pre- and post-cZi-DBS. Intelligibility was assessed through a transcription task performed by 32 naive listeners under two listening conditions: (i) with low-amplitude conversational speech added as background and (ii) with no added background noise. The listeners' responses were scored in terms of agreement with the intended words.Post-operatively, the total intelligibility score was significantly lower when cZi stimulation was switched on compared with off, for both listening conditions (with and without added background noise). Intelligibility was also significantly lower on stimulation compared with preoperative recordings, but only when assessed in the listening condition without background noise. The listening condition with added background noise resulted in significantly lower intelligibility scores compared with the no added noise condition for all stimulation conditions.The results of this study indicate that cZi-DBS in patients with PD can be detrimental to word-level speech intelligibility.

When a light source moves, the isophotes of the illuminance field (observed as “shading” in the case of Lambertian surfaces) move over the surfaces of illuminated objects. The sense of rotation of the isophotes relative to the sense of rotation of the “surface illuminance flow,” that is the tangential component of the illumination direction over the surface, depends on the Gaussian curvature of the surface. The temporal change of orientation, the “shading twist,” reveals this purely surface related quality. Since the shading twist depends only on the local curvature of the surface it doesn’t matter at all how the light source moves or where the light sources are, the “shading twist” is a pure surface property, that is to say, it behaves as being painted upon the surface. The formal relations pertaining to the shading twist are analyzed and a numerical simulation is presented that fully corroborates the conclusions from the formal study. The algorithm is also tested on a real scene.

Current modeling research in target marketing usually stresses the identification of profitable names for specific mailings. There is little recent research about the characteristics of typical direct mail (DM) customers. In this paper we determine the link between customers' socio-demographic characteristics and their propensity to purchase products through the mail. We hypothesize the existence of a latent variable, DM-proneness, which represents a consumer's tendency to shop via direct mail. Our model links the socio-demographics of customers to their self-reported purchase behavior through the latent variable of DM-proneness in a Multiple Indicators and Multiple Causes (MIMIC) model. We also introduce a second latent variable, DM information interest, which represents the desire to receive direct offers through the mail. The model allows for testing the influence of DM information interest on DM-proneness. We fit the model to actual consumer data using the LISREL program. The findings show that the ch...

In The Problem of Form (1893), the German sculptor Adolf Hildebrand distinguishes categorically between perception obtained from multiple fixations or vantage points (G.: Bewegungsvorstellungen; we call these ‘assemblages’), and from purely ‘iconic’ imagery (G.: Fernbilder). Only the latter he considers properly ‘artistic’. Hildebrand finds the reason for this ontological distinction in the microgenesis of visual awareness. What to make of this? We analyze the various ‘modes of seeing’ in some detail. The conceptual issues involved are fundamental, and relevant to both vision science and the visual arts.

SFS (Shape From Shading) theory is based upon the Lambertian paradigm. Our visual demonstrations imply that this paradigm fails to apply to the conventional stimuli used to probe vision. ispartof: i-Perception vol:4 issue:5 pages:299-302 ispartof: location:United States status: published

We study the “color weight” for a number of rather different paradigms. In well researched heterochromatic photometry methods we find that the “weights” determined by settings of naive observers are closely determined by the CIE luminance functional. This is very different for tasks that involve mid- and high-level aspects of perception. In several cases we find equipollence for the display red, green and blue channels. Moreover, in such cases the very nonlinear maximum-rule fits the data rather better than a linear functional. These findings are of interest when photometry needs to be applied for stimuli that are different from the high temporal and low spatial frequency gratings typical for flicker photometry. These results are relevant for science, ergonomics and art.

AimsOne goal of total hip arthroplasty is to restore normal hip anatomy. The aim of this study was to compare displacement of the centre of rotation (COR) using a standard reaming technique with a technique in which the acetabulum was reamed immediately peripherally and referenced off the rim.Patients and MethodsIn the first cohort the acetabulum was reamed to the floor followed by sequentially larger reamers. In the second cohort the acetabulum was only reamed peripherally, starting with a reamer the same size as the native femoral head. Anteroposterior pelvic radiographs were analysed for acetabular floor depth and vertical and horizontal position of the COR.ResultsHorizontally, the mean medial displacement of the COR was 0.8 mm (standard deviation (sd) 1.4) in the peripheral remaing group and 5.0 mm (sd 3.30) in the standard reaming group (p < 0.001). Vertically, the mean superior displacement of the COR was 0.7 mm (sd 1.3) in the peripheral reaming group and 3.7 mm (sd 2.6) in the standard reaming group (p < 0.001). In the standard reaming group, there was a strong correlation between the pre-operative acetabular floor depth and displacement of the COR (p < 0.001).ConclusionReaming the acetabulum to the floor can lead to significant displacement of the COR medially and superiorly. This displacement is related to the pre-operative acetabular floor depth and cannot always be compensated by using a high offset stem. Cite this article: Bone Joint J 2016;98-B:1597–603.

Cartoon-style line drawings contain very condensed information, after all most of the page stays blank. Yet, they constrain the contents of immediate visual awareness to an extraordinary extent. This is true even for drawings that are - though nominally "representational" - not even in central projection. Moreover, the strokes used in a drawing may stand for a bewildering variety of entities in the world. We studied Picasso drawings from the 1940s in which the artist famously combined multiple viewpoints. We find that the pictorial reliefs obtained from various observers agree to a large extent, and that the differences are of a very specific nature, typically involving variations in the mutual spatial attitudes of rigid body parts in figure studies. Although the purely planar layout of the drawings accounts for much of visual awareness, observers also use the sparse depth cues provided by the artist to evoke volumetric impressions. Observers also freely insert "template knowledge" about the structure of familiar generic objects. ispartof: Cognition vol:125 issue:3 pages:394-412 ispartof: location:Netherlands status: published

Human observers adjust the frontal view of a wireframe box on a computer screen so as to look equally deep and wide, so that in the intended setting the box looks like a cube. Perspective cues are limited to the size-distance effect, since all angles are fixed. Both the size on the screen, and the viewing distance from the observer to the screen were varied. All observers prefer a template view of a cube over a veridical rendering, independent of picture size and viewing distance. If the rendering shows greater or lesser foreshortening than the template, the box appears like a long corridor or a shallow slab, that is, like a 'deformed' cube. Thus observers ignore 'veridicality'. This does not fit an 'inverse optics' model. We discuss a model of 'vision as optical user interface'.

Shape from shading arose from artistic practice, and later experimental psychology, but its formal structure has only been established recently by computer vision. Some of its algorithms have led to useful applications. Psychology has reversely borrowed these formalisms in attempts to come to grips with shading as a depth cue. Results have been less than spectacular. The reason might well be that these formalisms are all based on Euclidean geometry and physics (radiometry), which, are the right tools in third person accounts, but have little relevance to first person accounts, and thus are biologically (and consequently psychologically) of minor interest. We propose a formal theory of the shading cue in the first person account, 'a view from the inside'. Such a perspective is also required for autonomous robots in AI. This formalism cannot be based on Euclidean geometry, nor on radiometry, but on the structure of pictorial space, and the structure of brightness space. The formalism, though different in kind, has a simple relation to the computer vision accounts. It has great robustness, is free from calibration issues, and allows purely local shape inferences. It is especially suited to biological (and thus AI) implementation. We consider a number of predictions and confront them with available empirical evidence.

Local space-time scrambling of optical data leads to violent jerks and dislocations. On masking these, visual awareness of the scene becomes cohesive, with dislocations discounted as amodally occluding foreground. Such cohesive space-time of awareness is technically illusory because ground truth is jumbled whereas awareness is coherent. Apparently the visual field is a construction rather than a (veridical) perception.

Human perception of sign language can serve as inspiration for the improvement of automatic recognition systems. Experiments with human signers show that sign language signs contain redundancy over time. In this article, experiments are conducted to investigate whether comparable redundancies also exist for an automatic sign language recognition system. Such redundancies could be exploited, for example, by reserving more processing resources for the more informative phases of a sign, or by discarding uninformative phases. In the experiments, an automatic system is trained and tested on isolated fragments of sign language signs. The stimuli used were similar to those of the human signer experiments, allowing us to compare the results. The experiments show that redundancy over time exists for the automatic recognizer. The central phase of a sign is the most informative phase, and the first half of a sign is sufficient to achieve a recognition performance similar to that of the entire sign. These findings concur with the results of the human signer studies. However, there are differences as well, most notably the fact that human signers score better on the early phases of a sign than the automatic system. The results can be used to improve the automatic recognizer, by using only the most informative phases of a sign as input.

The aim of this paper is to examine when signers start to recognize the lexical meaning of a sign. This is studied with movies of 32 mono-morphemic signs of Sign Language of the Netherlands (SLN). Signs were presented in isolation or with preceding fidgets (e.g., rubbing your nose). Signers watched these movies at normal playing speed and had to respond as soon as they recognized a sign, which they were able to do, on average, about 850 ms after the coded beginning of the sign. By subtracting the time participants need to generate a motor response to a visible event, which was 310 ms on average, sign recognition was estimated to occur after around 540 ms. The results were further analyzed in relation to the sign’s movement phases (preparation, nucleus, and recovery) and for effects of participant characteristics, sign characteristics, and embedding conditions. The current findings are compared with earlier work on the time course of lexical sign recognition. Moreover, they are compared with findings from an earlier experiment on detecting the beginning of a sign (Arendsen et al., 2007) to study possible interference of lexical recognition with sign detection by signers.

Background: Increased insulin-like growth factor (IGF)-I and IGF-II concentrations are related to increased colorectal cancer risk. Isoflavones have been associated with reduced colorectal cancer risk, and may affect the IGF system because of their weak estrogenic activity. The aim of the study was to investigate the effect of isolated isoflavones on serum concentrations of IGF system components.Materials and Methods: We conducted a randomized, placebo-controlled, double-blinded, crossover trial in four hospitals in the Netherlands to investigate the effect of an 8-week supplementation with red clover–derived isoflavones (84 mg/d) on serum IGF-I concentrations. In addition, serum concentrations of IGF-II and IGF binding proteins (IGFBP)-1, IGFBP-2, and IGFBP-3 were assessed. Normal colorectal tissue biopsies were obtained after the first intervention period and mRNA expression of IGF-I, IGF-II, IGFBP-3, and IGF-IR was evaluated. Our study population consisted of 34 postmenopausal women with a family history of colorectal cancer or a personal history of colorectal adenomas.Results: Isoflavone supplementation did not significantly affect serum concentrations of total IGF-I (mean relative within-person difference; IGF-I, −2.0%; 95% confidence interval, −8.0% to 3.9%). IGF-II and IGFBPs were also not significantly altered after isoflavone supplementation. Colorectal tissue mRNA expression of IGF system components did not significantly differ between individuals on isoflavone supplementation and those who received placebo.Conclusions: The results of our trial, supported by a qualitative review of soy trials published to date, suggest that isoflavones do not significantly affect circulating levels of IGF system components. Increased levels of IGF-I, as observed in most of these trials, are likely due to simultaneous protein supplementation. (Cancer Epidemiol Biomarkers Prev 2008;17(10):2585–93)

Background: Drotrecogin alfa activated (DrotAA) is licensed for treatment of patients with severe sepsis and organ failure. Among the latter, acute kidney injury (AKI), defined as the persistence of oligo-anuria following adequate resuscitation, is one of the most apprehended. We conducted a prospective, observational, and controlled study to test the hypothesis that DrotAA beneficially affected the evolution and outcome of AKI, complicating acute sepsis-induced cardiopulmonary failure. Methods: Forty-six patients were studied. Thirty subjects received standard treatment for sepsis without DrotAA. In the remaining 16 patients, DrotAA was added as a continuous infusion of 24 mg/kg/h for 96 h. Results: Mean age, causes of sepsis, and severity/organ failure scores were comparable between patients treated with or without DrotAA. Mortality at 28 days was high and comparable between both treatment groups (56% vs. 69%, DrotAA vs. no DrotAA; P 5 0.5). When oligo-anuria was present at the start of the study, it persisted during treatment in all patients, with no significant difference between groups. Both treatment groups presented with baseline mean daily fractional excretion of sodium values 42% that remained high during the observation period, regardless of whether DrotAA was given or not. Kidney histology showed a preserved renal architecture with tubular necrosis in all specimens. Similar glomerular, tubulo-interstitial, and vascular alterations were present in both treatment groups. Conclusion: In this small cohort of patients with severe sepsis who received adjuvant DrotAA treatment, no effect on urine output, tubular function, or mortality could be demonstrated.

The "visual space" of an optical observer situated at a single, fixed viewpoint is necessarily very ambiguous. Although the structure of the "visual field" (the lateral dimensions, i.e., the "image") is well defined, the "depth" dimension has to be inferred from the image on the basis of "monocular depth cues" such as occlusion, shading, etc. Such cues are in no way "given", but are guesses on the basis of prior knowledge about the generic structure of the world and the laws of optics. Thus such a guess is like a hallucination that is used to tentatively interpret image structures as depth cues. The guesses are successful if they lead to a coherent interpretation. Such "controlled hallucination" (in psychological terminology) is similar to the "analysis by synthesis" of computer vision. Although highly ambiguous, visual spaces do have geometrical structure. The group of ambiguities left open by the cues (e.g., the well known bas-relief ambiguity in the case of shape from shading) may be interpreted as the group of congruences (proper motions) of the space. The general structure of visual spaces for different visual fields is explored in the paper. Applications include improved viewing systems for optical man-machine interfaces.

We studied if and when people detect the beginning of a gesture, in our case a sign in Sign Language of the Netherlands (SLN), by presenting movie fragments consisting of sequences of rest positions, fidgets, and signs to deaf signers, hearing signers and non-signers. Participants were instructed to respond as soon as they saw that a SLN sign had begun. All participants showed themselves highly capable of responding to sign beginnings. Signs that are two-handed, performed in signing space, have a highly marked hand shape, and contain path movement were discriminated best. Considering a sign as having a preparation, a stroke, and a recovery, response times showed strong clusters around 500 milliseconds after the beginning of sign preparation, or 200 ms after the onset of the stroke. The non-signers needed more time before responding; deaf signers took more time than hearing signers. Response time was influenced by three factors (shorter for signs that have a highly marked hand shape, are one-handed, and are preceded by fidgets). The results show that it is possible for people to discriminate fidgeting and signs based on appearance, even if one does not know sign language. No single feature of the movement appears necessary to detect the beginning of a sign. In most cases visual information available up to an early stage of the stroke is sufficient but in some cases the information in the preparation is enough.

In this paper we will present an overview of our research into perception and biologically inspired modeling of illumination (flow) from 3D textures and the influence of roughness and illumination on material perception. Here 3D texture is defined as an image of an illuminated rough surface. In a series of theoretical and empirical papers we studied how we can estimate the illumination orientation (in the image plane) from 3D textures of globally flat samples. We found that the orientation can be estimated well by humans and computers using an approach based on second order statistics. This approach makes use of the dipole-like structures in 3D textures that are the results of illumination of bumps / throughs. For 3D objects, the local illumination direction varies over the object, resulting in surface illuminance flow. This again results in image illuminance flow in the image of a rough 3D object: the observable projection in the image of the field of local illumination orientations. Here we present results on image illuminance flow analysis for images from the Utrecht Oranges database, the Curet database and two vases. These results show that the image illuminance flow can be estimated robustly for various rough materials. In earlier studies we have shown that the image illuminance flow can be used to do shape and illumination inferences. Recently, in psychophysical experiments we found that adding 3D texture to a matte spherical object improves judgments of the direction and diffuseness of its illumination by human observers. This shows that human observers indeed use the illuminance flow as a cue for the illumination.

We report final event-driven analysis data on the immunogenicity and efficacy of the human papillomavirus 16 and 18 ((HPV-16/18) AS04-adjuvanted vaccine in young women aged 15 to 25 years from the PApilloma TRIal against Cancer In young Adults (PATRICIA). The total vaccinated cohort (TVC) included all randomized participants who received at least one vaccine dose (vaccine, n = 9,319; control, n = 9,325) at months 0, 1, and/or 6. The TVC-naive (vaccine, n = 5,822; control, n = 5,819) had no evidence of high-risk HPV infection at baseline, approximating adolescent girls targeted by most HPV vaccination programs. Mean follow-up was approximately 39 months after the first vaccine dose in each cohort. At baseline, 26% of women in the TVC had evidence of past and/or current HPV-16/18 infection. HPV-16 and HPV-18 antibody titers postvaccination tended to be higher among 15- to 17-year-olds than among 18- to 25-year-olds. In the TVC, vaccine efficacy (VE) against cervical intraepithelial neoplasia grade 1 or greater (CIN1+), CIN2+, and CIN3+ associated with HPV-16/18 was 55.5% (96.1% confidence interval [CI], 43.2, 65.3), 52.8% (37.5, 64.7), and 33.6% (−1.1, 56.9). VE against CIN1+, CIN2+, and CIN3+ irrespective of HPV DNA was 21.7% (10.7, 31.4), 30.4% (16.4, 42.1), and 33.4% (9.1, 51.5) and was consistently significant only in 15- to 17-year-old women (27.4% [10.8, 40.9], 41.8% [22.3, 56.7], and 55.8% [19.2, 76.9]). In the TVC-naive, VE against CIN1+, CIN2+, and CIN3+ associated with HPV-16/18 was 96.5% (89.0, 99.4), 98.4% (90.4, 100), and 100% (64.7, 100), and irrespective of HPV DNA it was 50.1% (35.9, 61.4), 70.2% (54.7, 80.9), and 87.0% (54.9, 97.7). VE against 12-month persistent infection with HPV-16/18 was 89.9% (84.0, 94.0), and that against HPV-31/33/45/51 was 49.0% (34.7, 60.3). In conclusion, vaccinating adolescents before sexual debut has a substantial impact on the overall incidence of high-grade cervical abnormalities, and catch-up vaccination up to 18 years of age is most likely effective. (This study has been registered at ClinicalTrials.gov under registration no. NCT001226810.)

Three human observers estimated the illumination direction for samples of random Gaussian surfaces illuminated by a collimated beam from random directions. These stimuli appear as ‘texture’ due to shading and shadowing (the surface on the microscale was Lambertian of uniform albedo; thus texture appears only through shading and shadowing). We found that observers were able to estimate the azimuth of the source with remarkable accuracy. In the shading regime (no shadows) the observers committed 180° azimuth errors with 50% probability, whereas in the shadow-dominated regime they were able to avoid this convex/concave confusion to a large extent. They evidently relied on second-order statistics in the shading regime and used an unidentified first-order cue in the shadow regime. The elevations of the source were also estimated with remarkable precision. We attribute this to the statistical homogeneity of the sample which can apparently be exploited by the observers. Likely cues are the fraction of shadowed surface, average intensity and rms contrast. The ability of human observers to estimate the illumination direction from surface texture no doubt contributes to the ability to estimate the light field in scenes, which is a prerequisite to the photometric parsing of scenes (shape from shading, and so forth).

Insulin-like growth factors (IGFs) play an important role in tumour growth and development. We hypothesized that this is also the case for medulloblastomas, which are highly malignant cerebellar brain tumours usually occurring in children. In these tumours the expression patterns of IGF-I and -II mRNA were studied. Tumour specimens obtained from 12 children and two adults at diagnosis were hybridized in situ with digoxigenin-labelled cRNA probes for hIGF-I and hIGF-II mRNAs. In all cases, tumour cells showed abundant expression of IGF-I mRNA. Nine of the 14 tumours showed variable but significant IGF-II expression. In these tumours, the hybridization signal almost exclusively colocalized with a subpopulation of Ki-M1P positive cells that were identified as ramified microglia (RM) cells. In the five tumours without IGF-II expression, microglia/brain macrophages with a more rounded amoeboid-like morphology predominated. RM cells in normal cerebellar tissues, residing abundantly in areas of the white and, to a less extent, in the grey matter, were IGF-II mRNA-negative. These RM cells showed a thinner and more extensively branched appearance and were more evenly distributed than those encountered in medulloblastoma. Probably, during the transformation from the resting ramified towards the amoeboid morphology (or vice versa) IGF-II mRNA expression is only temporarily induced. The physiological meaning of the induction of IGF-II mRNA expression by these cells in medulloblastoma remains unclear but any IGF-II peptide synthesized could exert unfavourable mitogenic and antiapoptotic effects on adjacent tumour cells. However, in this relatively small number of cases we could not find any indications for a relationship between clinical characteristics of the various cases and the extent of IGF-II mRNA expression.

iceA1 in Helicobacter pylori is a homolog of nlaIIIR, which encodes the CATG-specific restriction endonuclease NlaIII in Neisseria lactamica. Analysis of iceA1 sequences from 49 H.pylori strains shows that a full-length NlaIII-like ORF is present in 10 strains, including CH4, but in other strains, including strain 60190, the ORFs are truncated due to a variety of mutations. Our goal was to determine whether iceA1 can encode a NlaIII-like endonuclease. Overexpression in Escherichia coli of iceA1 from CH4, but not from 60190, yielded NlaIII-like activity, indicating that the full-length iceA1 is a functional endonuclease gene. Repair of the iceA1 frameshift mutation in strain 60190 and its expression in E.coli yielded functional NlaIII-like activity. We conclude that iceA1 in CH4 is a functional restriction endonuclease gene, while iceA1 in 60190 is not, due to a frameshift mutation, but that its repair restores its restriction endonuclease activity.

Summary objective and patients To assess multiple dose–response relationships between three GH doses (1·5, 3·0 and 6·0 IU/m2) and nine different biochemical markers of GH sensitivity in a well-defined group of 17 children with idiopathic short stature (ISS). design and measurements Serum levels of IGF-I, IGF-II and IGFBP-3, and peripheral markers leptin, C-terminal propeptide of type I collagen (PICP) and N-terminal propeptide of type III collagen (PIIINP), alkaline phosphatase (AP) and osteocalcin (OC) were measured at the start and after 2 and 12 weeks of periods of no treatment, GH 1·5 IU/m2 and GH 3·0 IU/m2. Twelve-week washout periods were applied between the 12-week GH-treatment periods. High-dose GH treatment was given during the second year of study and all serum markers were measured at start, after 2 and 12 weeks and 1 year of GH 6·0 IU/m2. In 18 non-GH-treated children with ISS the same parameters were measured yearly. The bone resorption marker urinary deoxypyridinoline (DPD) was measured during 12-h day and night periods at start and after 2 weeks GH 1·5, 3·0 and 6·0 IU/m2. results All markers were GH dependent, but the timing of maximal response varied among different markers. Height SDS at start, age at start and IGF-II at baseline were inversely related to the first-year growth response (r = −0·73, P = 0·001; r = −0·53, P = 0·03; and r = −0·53, P = 0·03, respectively). Some statistically significant correlations between biochemical responses on low GH doses (1·5 or 3·0 IU/m2) and second-year growth response were found, but these showed no consistent pattern. However, all changes in IGF-I SDS after GH 6·0 IU/m2 measured either after 2 or 12 weeks or 1 year correlated significantly with the second-year growth response (r = 0·55, P = 0·02; r = 0·81, P = 0·001; and r = 0·86, P

We report the initial results of an ongoing randomised, prospective study on migration of the Exeter and Elite Plus femoral stems after impaction allografting, as measured by radiostereometry. Clinically, the impaction technique gave good results for both stems. The mean subsidence in the first year was 1.30 mm and 0.20 mm for the Exeter and the Elite Plus stems, respectively. In the second year, the Exeter stem continued to subside further by a mean of 0.42 mm, while the Elite Plus stem did not do so. Subsidence of the Exeter stem correlated with deficiency of bone stock as graded on the Gustilo and Pasternak scale. This correlation was not found for the Elite Plus stem. None of the other parameters which were studied predisposed to subsidence. There was no significant association between the amount of subsidence and the radiological appearance of the graft for either stem. Our findings do not support the theory that radial compression, due to subsidence of the Exeter stem, is the essential stimulus for remodelling in impaction allografting.

Septic shock is the most severe clinical manifestation of meningococcal disease and is predominantly seen in children under 5 yr of age. Very limited research has been performed to elucidate the alterations of the GH/IGF-I axis in critically ill children. We evaluated the GH/IGF-I axis and the levels of IGF-binding proteins (IGFBPs), IGFBP-3 protease, glucose, insulin, and cytokines in 27 children with severe septic shock due to meningococcal sepsis during the first 3 d after admission. The median age was 22 months (range, 4-185 months). Eight patients died. Nonsurvivors had extremely high GH levels that were significant different compared with mean GH levels in survivors during a 6-h GH profile (131 vs. 7 mU/liter; P0.01). Significant differences were found between nonsurvivors and survivors for the levels of total IGF-I (2.6 vs. 5.6 nmol/liter), free IGF-I (0.003 vs. 0.012 nmol/liter), IGFBP-1 (44.3 vs. 8.9 nmol/liter), IGFBP-3 protease activity (61 vs. 32%), IL-6 (1200 vs. 50 ng/ml), and TNFalpha (34 vs. 5.3 pg/ml; P0.01). The pediatric risk of mortality score correlated significantly with levels of IGFBP-1, IGFBP-3 protease activity, IL-6, and TNFalpha (r = +0.45 to +0.69) and with levels of total IGF-I and free IGF-I (r = -0.44 and -0.55, respectively). Follow-up after 48 h in survivors showed an increased number of GH peaks, increased free IGF-I and IGFBP-3 levels, and lower IGFBP-1 levels compared with admission values. GH levels and IGFBP-1 levels were extremely elevated in nonsurvivors, whereas total and free IGF-I levels were markedly decreased and were accompanied by high levels of the cytokines IL-6 and TNFalpha. These values were different from those for the survivors. Based on these findings and literature data a hypothetical model was constructed summarizing our current knowledge and understanding of the various mechanisms.

Childhood celiac disease may lead to a failure of statural growth. After institution of a gluten-free diet most patients exhibit catch-up growth. Catch-up growth is a remarkable phenomenon characterized by a supranormal height velocity. One of the hypothetical mechanisms of catch-up growth is that an increased activity of the somatotrophic axis is involved. In order to provide further insight in the physiology of catch-up growth, auxological and endocrine changes were prospectively studied in 28 children with newly diagnosed celiac disease. The results demonstrate a malnutrition-like state of the somatotrophic axis at the time of diagnosis and a rapid recovery of this axis towards normal functioning after institution of the gluten-free diet. Although several correlations between these endocrine alterations and auxological parameters were detected, it is questionable whether the endocrine changes are the driving force behind catch-up growth.

We studied effects of dark adaptation on spatial and temporal tuning for motion coherence detection. We compared tuning for step size and delay for moving random pixel arrays (RPAs) at two adaptation levels, one light adapted (50 cd/m2) and the other relatively dark adapted (0.05 cd/m2). To study coherence detection rather than contrast detection, RPAs were scaled for equal contrast detection at each luminance level, and a signal-to-noise ratio paradigm was used in which the RPA is always at a fixed, supra-threshold contrast level. The noise consists of a spatio-temporally incoherent RPA added to the moving RPA on a pixel-by-pixel basis. Spatial and temporal limits for coherence detection were measured using a single step pattern lifetime stimulus, in which patterns on alternate frames make a coherent step and are being refreshed. Therefore, the stimulus contains coherent motion at a single combination of step size and delay only.The main effect of dark adaptation is a large shift in step size, slightly less than the adjustment of spatial scale required for maintaining equal contrast sensitivity. A similar change of preferred step size occurs also for scaled stimuli at a light-adapted level, indicating that the spatial effect is not directly linked to dark adaptation, but more generally related to changes in the available low-level spatial information. Dark-adaptation shifts temporal tuning by about a factor of 2. Long delays are more effective at low luminance levels, whereas short delays no longer support motion coherence detection. Luminance-invariant velocity tuning curves, as reported previously [Lankheet, M.J.M., van Doorn, A.J., Bouman, M.A., & van de Grind, W.A. (2000) Motion coherence detection as a function of luminance in human central vision. Vision Research, 40, 3599–3611], result from recruitment of different sets of motion detectors, and an adjustment of their temporal properties.

IGF-I is mainly sequestered in a 150-kDa ternary complex with IGF binding protein (IGFBP)-3 and the acid-labile subunit. Data on complex formation and factors influencing formation have not been established. Dissociation of IGF-I from the ternary complex is in part regulated by proteolysis of IGFBP-3, which reduces its affinity for IGF-I. Short small for gestational age (SGA) children have lower IGF-I and IGFBP-3 levels compared with healthy peers.The objective of the study was to determine complex formation in healthy normal-statured children and assess variables influencing complex formation. Second, we determined complex formation in short SGA children.Complex formation was assessed using (125)I-hIGF-I column chromatography in 70 controls (40 boys), median age 10.6 years, and 40 short SGA children (25 boys), median age 8.6 years. IGFBP-3 was determined by Western immunoblotting.(125)I-hIGF-I complex formation showed an age-specific pattern in healthy controls. Variables positively influencing ternary complex formation were higher serum IGF-I levels compared with IGFBP-3 levels (P.001) and lower serum IGF-II (P.001) and IGFBP-1 levels (P.001). In addition, a higher presence of proteolyzed IGFBP-3 negatively influenced 150-kDa complex formation (P = .006). At a young age, healthy children showed considerable IGFBP-3 proteolytic activity, which declined with aging (P.001). IGFBP-3 proteolytic activity was negatively correlated with IGF-I levels (P.001). Compared with healthy controls, short SGA children showed reduced IGF-I levels (-1.3 vs 0.1 SD score) and increased proteolyzed IGFBP-3 (35.1% vs 12.2%).Age-specific normative values for (125)I-hIGF-I 150-kDa ternary complex formation are presented. A decrease in IGF-I and an increase in IGF-II, IGFBP-1, and IGFBP-3 proteolytic activity associate with reduced (125)I-hIGF-I ternary complex formation. Our results suggest that in conditions in which IGF-I levels are low, such as young age and in short SGA children, IGFBP-3 proteolytic activity is increased to ensure IGF-I bioavailability.

When you open your eyes in bright daylight, you become visually aware of the scene in front of you. That is to say, generically, for you might be blind, hallucinate, and so forth. To many people visual awareness appears three-fold extended in space, and evolving over time. One makes out objects and processes in intricate interrelations. Here we are mainly interested in immediate visual awareness of the type that happens when you look at a painting. We assume you close one eye and hold your position with respect to the canvas. This restriction cuts down on the complexity, for instance, it plays down the importance of visuomotor factors, binocular multiperspective, and scene changes.

Aims: To determine acid-labile subunit (ALS) levels in short small for gestational age (SGA) children and to assess the relationship between ALS levels and several clinical and laboratory characteristics. Also, to assess whether adding ALS levels to a growth prediction model might improve the long-term growth prediction. Design/Methods: ALS levels were measured in 312 short SGA children at the start of growth hormone (GH) treatment. Results: Median (interquartile range) ALS of all subjects was -0.5 SDS, significantly below the 0 SDS (p < 0.001). In 34 children (11%), ALS levels were ≤-2 SDS. ALS SDS correlated significantly with height SDS (r = 0.24, p < 0.001), weight SDS (r = 0.30, p < 0.001), BMI SDS (r = 0.20, p = 0.001), IGF-I SDS (r = 0.56, p < 0.001) and IGFBP-3 SDS (r = 0.67, p < 0.001). ALS SDS was also positively correlated with fasting insulin (r = 0.41, p < 0.001) and glucose levels (r = 0.33, p < 0.001), and HOMA-IR (r = 0.35, p < 0.001). Baseline ALS levels contributed to the long-term growth prediction of GH treatment (5%, p < 0.001). Conclusion: Short SGA children tend to have lower ALS levels compared to controls, albeit less reduced than IGF-I and IGFBP-3 levels. Our data suggest that ALS may be involved in glucose homeostasis. Determination of ALS levels before the start of GH treatment in short SGA children contributes moderately to a more accurate prediction of the growth response to GH treatment.