An essay concerning human understanding. And A treatise on the conduct of the understanding.

At head of title: Locke's essays.

Molecular introduction to head and neck cancer (HNSCC) carcinogenesis

Of all human cancers, HNSCC is the most distressing affecting pain, disfigurement, speech and the basic survival functions of breathing and swallowing. Mortality rates have not significantly changed in the last 40 years despite advances in radiotherapy and surgical treatment. Molecular markers are currently being identified that can determine prognosis preoperatively by routine tumour biopsy Leading to improved management of HNSCC patients. The approach could help decide which early stage patient should have adjuvant neck dissection and radiotherapy, and whether Later stage patients with operable lesions would benefit from resection and reconstructive surgery or adopt a conservative approach to patients with poor prognosis regardless of treatment. In the future, understanding these basic genetic changes in HNSCC would be important for the management of HNSCC. (C) 2004 The British Association of Plastic Surgeons. Published by Elsevier Ltd. All rights reserved.

The head and body lice of humans are genetically distinct (Insecta : Phthiraptera, Pediculidae): evidence from double infestations

Little is known about the population genetics of the louse infestations of humans. We used microsatellite DNA to study 11 double infestations, that is, hosts infested with head lice and body lice simultaneously. We tested for population structure on a host, and for population structure among seven hosts that shared sleeping quarters. We also sought evidence of migration among louse populations. Our results showed that: (i) the head and body lice on these individual hosts were two genetically distinct populations; (ii) each host had their own populations of head and body lice that were genetically distinct to those on other hosts; and (iii) lice had migrated from head to head, and from body to body, but not between heads and bodies. Our results indicate that head and body lice are separate species.

Novel markers for poor prognosis in head and neck cancer

Head and neck cancer (HNSCC) is one of the most distressing human cancers, causing pain and affecting the basic survival functions of breathing and swallowing. Mortality rates have not changed despite recent advances in radiotherapy and surgical treatment. We have compared the expression of over 13,000 unique genes in 7 cases of matched HNSCC and normal oral mucosa. Of the 1,260 genes that showed statistically significant differences in expression between normal and tumor tissue at the mRNA level, the three top ranking of the top 5% were selected for further analysis by immunohistochemistry on paraffin sections,. along with the tumor suppressor genes p16 and p53, in a total of 62 patients including 55 for whom >4-year clinical data was available. Using univariate and multivariate survival analysis, we identified SPARC/osteonectin as a powerful independent prognostic marker for short disease-free interval (DFI) (p < 0.002) and poor overall survival (OS) (p = 0.018) of HNSCC patients. In combination with other ECM proteins found in our analysis, PAI-1 and uPA, the association with DFI and OS became even more significant (p < 0.001). Our study represents the first instance of SPARC as an independent prognostic marker in HNSCC.

Head and neck cancer: past, present and future

Head and neck cancer consists of a diverse group of cancers that ranges from cutaneous, lip, salivary glands, sinuses, oral cavity, pharynx and larynx. Each group dictates different management. In this review, the primary focus is on head and neck squamous cell carcinoma (HNSCC) arising from the mucosal lining of the oral cavity and pharynx, excluding nasopharyngeal cancer. Presently, HNSCC is the sixth most prevalent neoplasm in the world, with approximately 900,000 cases diagnosed worldwide. Prognosis has improved little in the past 30 years. In those who have survived, pain, disfigurement and physical disability from treatment have had an enormous psychosocial impact on their lives. Management of these patients remains a challenge, especially in developing countries where this disease is most common. Of all human cancers, HNSCC is the most distressing since the head and neck is the site of the most complex functional anatomy in the human body. Its areas of responsibility include breathing, the CNS, vision, hearing, balance, olfaction, taste, swallowing, voice, endocrine and cosmesis. Cancers that occur in this area impact on these important human functions. Consequently, in treating cancers of the head and neck, the effects of the treatment on the functional outcome of the patient need the most serious consideration. In assessing the success of HNSCC treatment, consideration of both the survival and functional deficits that the patient may suffer as a consequence of their treatment are of paramount importance. For this reason, the modern-day management of head and neck patients should be carried out in a multidisciplinary head and neck clinic.

Illusory changes in head position induced by neck muscle vibration can alter the perception of elbow position

Acuity for elbow joint position sense (JPS) is reduced when head position is modified. Movement of the head is associated with biomechanical changes in the neck and shoulder musculoskeletal system, which may explain changes in elbow JPS. The present study aimed to determine whether elbow JPS is also influenced by illusory changes in head position. Simultaneous vibration of sternocleidomastoid (SCM) and the contralateral splenius was applied to 14 healthy adult human subjects. Muscle vibration or passive head rotation was introduced between presentation and reproduction of a target elbow position. Ten out of 14 subjects reported illusions consistent with lengthening of the vibrated muscles. In these 10 subjects, absolute error for elbow JPS increased with left SCM/right splenius vibration but not with right SCM/left splenius vibration. Absolute error also increased with right rotation, with a trend for increased error with left rotation. These results demonstrated that both actual and illusory changes in head position are associated with diminished acuity for elbow JPS, suggesting that the influence of head position on upper limb JPS depends, at least partially, on perceived head position.

The role of oscillatory brain activity in object processing and figure-ground segmentation in human vision

The perception of an object as a single entity within a visual scene requires that its features are bound together and segregated from the background and/or other objects. Here, we used magnetoencephalography (MEG) to assess the hypothesis that coherent percepts may arise from the synchronized high frequency (gamma) activity between neurons that code features of the same object. We also assessed the role of low frequency (alpha, beta) activity in object processing. The target stimulus (i.e. object) was a small patch of a concentric grating of 3c/°, viewed eccentrically. The background stimulus was either a blank field or a concentric grating of 3c/° periodicity, viewed centrally. With patterned backgrounds, the target stimulus emerged--through rotation about its own centre--as a circular subsection of the background. Data were acquired using a 275-channel whole-head MEG system and analyzed using Synthetic Aperture Magnetometry (SAM), which allows one to generate images of task-related cortical oscillatory power changes within specific frequency bands. Significant oscillatory activity across a broad range of frequencies was evident at the V1/V2 border, and subsequent analyses were based on a virtual electrode at this location. When the target was presented in isolation, we observed that: (i) contralateral stimulation yielded a sustained power increase in gamma activity; and (ii) both contra- and ipsilateral stimulation yielded near identical transient power changes in alpha (and beta) activity. When the target was presented against a patterned background, we observed that: (i) contralateral stimulation yielded an increase in high-gamma (>55 Hz) power together with a decrease in low-gamma (40-55 Hz) power; and (ii) both contra- and ipsilateral stimulation yielded a transient decrease in alpha (and beta) activity, though the reduction tended to be greatest for contralateral stimulation. The opposing power changes across different regions of the gamma spectrum with 'figure/ground' stimulation suggest a possible dual role for gamma rhythms in visual object coding, and provide general support of the binding-by-synchronization hypothesis. As the power changes in alpha and beta activity were largely independent of the spatial location of the target, however, we conclude that their role in object processing may relate principally to changes in visual attention.

Sun and sky:does human vision assume a mixture of point and diffuse illumination when interpreting shape-from-shading?

People readily perceive smooth luminance variations as being due to the shading produced by undulations of a 3-D surface (shape-from-shading). In doing so, the visual system must simultaneously estimate the shape of the surface and the nature of the illumination. Remarkably, shape-from-shading operates even when both these properties are unknown and neither can be estimated directly from the image. In such circumstances humans are thought to adopt a default illumination model. A widely held view is that the default illuminant is a point source located above the observer's head. However, some have argued instead that the default illuminant is a diffuse source. We now present evidence that humans may adopt a flexible illumination model that includes both diffuse and point source elements. Our model estimates a direction for the point source and then weights the contribution of this source according to a bias function. For most people the preferred illuminant direction is overhead with a strong diffuse component.

Continuous measurement of accommodation in human factor applications

It has long been sought to measure ocular accommodation continuously in human factor applications such as driving or flying. Open-field autorefractors such as the Canon R-1 could be converted to allow continuous, objective recording, but steady eye fixation and head immobilisation were essential for the measurements to be valid. Image analysis techniques utilised by newer open-view autorefractors such as the Shin-Nippon SRW-5000 are more tolerant to head and eye movements, but perhaps the technique with the greatest potential for the measurement of accommodation in human factor applications is photoretinoscopy. This paper examines the development of techniques for high temporal measurements of accommodation and reports on the tolerance of one such recent commercial instrument, the PowerRefractor (PlusOptiX). The instrument was found to be tolerant to eye movements from the optical axis of the instrument (∼0.50 DS change in apparent accommodation with gaze 25° eccentric to the optical axis), longitudinal head movement (<0.25 DS from 8 cm towards and 20 cm away from the correct photorefractor to eye distance) and changes in background illuminance (<0.25 DS from 0.5 to 20 cd m-2 target luminance). The PowerRefractor also quantifies the direction of gaze and pupil size, but is unable to take measurements with small pupils <3.7 ±1.0 mm. © 2002 The College of Optometrists.

The development of constrained source localisation algorithms for human brain imaging

This work sets out to evaluate the potential benefits and pit-falls in using a priori information to help solve the Magnetoencephalographic (MEG) inverse problem. In chapter one the forward problem in MEG is introduced, together with a scheme that demonstrates how a priori information can be incorporated into the inverse problem. Chapter two contains a literature review of techniques currently used to solve the inverse problem. Emphasis is put on the kind of a priori information that is used by each of these techniques and the ease with which additional constraints can be applied. The formalism of the FOCUSS algorithm is shown to allow for the incorporation of a priori information in an insightful and straightforward manner. In chapter three it is described how anatomical constraints, in the form of a realistically shaped source space, can be extracted from a subject’s Magnetic Resonance Image (MRI). The use of such constraints relies on accurate co-registration of the MEG and MRI co-ordinate systems. Variations of the two main co-registration approaches, based on fiducial markers or on surface matching, are described and the accuracy and robustness of a surface matching algorithm is evaluated. Figures of merit introduced in chapter four are shown to given insight into the limitations of a typical measurement set-up and potential value of a priori information. It is shown in chapter five that constrained dipole fitting and FOCUSS outperform unconstrained dipole fitting when data with low SNR is used. However, the effect of errors in the constraints can reduce this advantage. Finally, it is demonstrated in chapter six that the results of different localisation techniques give corroborative evidence about the location and activation sequence of the human visual cortical areas underlying the first 125ms of the visual magnetic evoked response recorded with a whole head neuromagnetometer.

Functional localisation of human sensory-motor cortex using magnetoencephalography

The 19 channel Neuromagnetometer system in the Clinical Neurophysiology Unit at Aston University is a multi-channel system, unique in the United Kingdom. A bite bar head localisation and MRI co-registration strategy which enabled accurate and reproducible localisation of MEG data into cortical space was developed. This afforded the opportunity to study magnetic fields of the human cortex generated by stimulation of peripheral nerve, by stimulation of visceral sensory receptors and by those evoked through voluntary finger movement. Initially, a study of sensory-motor evoked data was performed in a healthy control population. The techniques developed were then applied to patients who were to undergo neurosurgical intervention for the treatment of epilepsy and I or space occupying lesions. This enabled both validation of the effective accuracy of source localisation using MEG as well as to determine the clinical value of MEG in presurgical assessment of functional localisation in human cortex. The studies in this thesis have demonstrated that MEG can repeatedly and reliably locate sources contained within a single gyrus and thus potentially differentiate between disparate gyral activation. This ability is critical in the clinical application of any functional imaging technique; which is yet to be fully validated by any other 'non-invasive' functional imaging methodology. The technique was also applied to the study of visceral sensory representation in the cortex which yielded important data about the multiple cortical representation of visceral sensory function.

Assessment of the oculomotor response in human factor environments

The need to measure the response of the oculomotor system, such as ocular accommodation, accurately and in real-world environments is essential. New instruments have been developed over the past 50 years to measure eye focus including the extensively utilised and well validated Canon R-1, but in general these have had limitations such as a closed field-of-view, a poor temporal resolution and the need for extensive instrumentation bulk preventing naturalistic performance of environmental tasks. The use of photoretinoscopy and more specifically the PowerRefractor was examined in this regard due to its remote nature, binocular measurement of accommodation, eye movement and pupil size and its open field-of-view. The accuracy of the PowerRefractor to measure refractive error was on averaging similar, but more variable than subjective refraction and previously validated instrumentation. The PowerRefractor was found to be tolerant to eye movements away from the visual axis, but could not function with small pupil sizes in brighter illumination. The PowerRefractor underestimated the lead of accommodation and overestimated the slope of the accommodation stimulus response curve. The PowerRefractor and the SRW-5000 were used to measure the oculomotor responses in a variety of real-world environment: spectacles compared to single vision contract lenses; the use of multifocal contact lenses by pre-presbyopes (relevant to studies on myopia retardation); and ‘accommodating’ intraocular lenses. Due to the accuracy concerns with the PowerRefractor, a purpose-built photoretinoscope was designed to measure the oculomotor response to a monocular head-mounted display. In conclusion, this thesis has shown the ability of photoretinoscopy to quantify changes in the oculomotor system. However there are some major limitations to the PowerRefractor, such as the need for individual calibration for accurate measures of accommodation and vergence, and the relatively large pupil size necessary for measurement.

Physiological and pathological human ocular perfusion characteristics

There were three principle aims to this thesis. Firstly, the acquisition protocols of clinical blood flow apparatus were investigated in order to optimise them for both cross-sectional and longitudinal application. Secondly, the effects of physiological factors including age and systematic circulation on ocular blood flow were investigated. Finally, the ocular perfusion characteristics of patients diagnosed with ocular diseases considered to be of a vascular origin were investigated. The principle findings of this work are:- 1) Optimisation of clinical investigationsPhotodiode sensitivity of the scanning laser Doppler flowmeter should be kept within a range of 70-150 DC when acquiring images of the retina and optic nerve head in order to optimise the reproducibility of capillary blood flow measures. Account of the physiological spatial variation in retinal blood flow measures can be made using standard analysis protocols of the scanning laser Doppler flowmeter combined with a local search strategy. Measurements of pulsatile ocular blood flow using the ocular blood flow analyser are reproducible, however this reproducibility can be improved when consecutive intraocular pressure pulses are used to calculate pulsatile ocular blood flow. Spectral analysis of the intraocular pressure pulse-wave is viable and identifies the first four harmonic components of the waveform. 2) Physiological variation in ocular perfusionAge results in a significant reduction in perfusion of the retinal microcirculation, which is not evident in larger vessel beds such as the choroid. Despite known asymmetry in the systemic vasculature, no evidence of interocular asymmetry in ocular perfusion is apparent. 3) Pathological variation in ocular perfusionIn primary open angle glaucoma, perfusion is reduced in the retinal microcirculation of patients classified as having early to moderate visual field defects. However, ocular pulsatility defects are masked when patients and subjects are matched for systemic variables (pulse rate and mean arterial pressure); differentiation is facilitated by the application of waveform analysis to the continuos intraocular pressure curve even in the early stages of disease. Diabetic patients with adequate glycaemic control, exhibit maintenance of macular blood flow, macular topography and visual function following phacoemulsification.

Characterization of tissue transglutaminase in human osteoblast-like cells

Tissue transglutaminase (tTG) is a calcium-dependent and guanosine 5'-triphosphate (GTP) binding enzyme, which catalyzes the post-translational modification of proteins by forming intermolecular ε(ϒ-glutamyl)lysine cross-links. In this study, human osteoblasts (HOBs) isolated from femoral head trabecular bone and two osteosarcoma cell lines (HOS and MG-63) were studied for their expression and localization of tTG. Quantitative evaluation of transglutaminase (TG) activity determined using the [1,414C]-putrescine incorporation assay showed that the enzyme was active in all cell types. However, there was a significantly higher activity in the cell homogenates of MG-63 cells as compared with HOB and HOS cells (p <0.001). There was no significant difference between the activity of the enzyme in HOB and HOS cells. All three cell types also have a small amount of active TG on their surface as determined by the incorporation of biotinylated cadaverine into fibronectin. Cell surface-related tTG was further shown by preincubation of cells with tTG antibody, which led to inhibition of cell attachment. Western blot analysis clearly indicated that the active TG was tTG and immunocytochemistry showed it be situated in the cytosol of the cells. In situ extracellular enzyme activity also was shown by the cell-mediated incorporation of fluorescein cadaverine into extracellular matrix (ECM) proteins. These results clearly showed that MG-63 cells have high extracellular activity, which colocalized with the ECM protein fibronectin and could be inhibited by the competitive primary amine substrate putrescine. The contribution of tTG to cell surface/matrix interactions and to the stabilization of the ECM of osteoblast cells therefore could by an important factor in the cascade of events leading to bone differentiation and mineralization.