Dynamics of Fluorescent Imaging for Rapid Tear Thinning.

A previous mathematical model has successfully simulated the rapid tear thinning caused by glob (thicker lipid) in the lipid layer. It captured a fast spreading of polar lipid and a corresponding strong tangential flow in the aqueous layer. With the simulated strong tangential flow, we now extend the model by adding equations for conservation of solutes, for osmolarity and fluorescein, in order to study their dynamics. We then compare our computed results for the resulting intensity distribution with fluorescence experiments on the tear film. We conclude that in rapid thinning, the fluorescent intensity can linearly approximate the tear film thickness well, when the initial fluorescein concentration is small. Thus, a dilute fluorescein is recommended for visualizing the rapid tear thinning during fluorescent imaging.

Duplex Tear Film Evaporation Analysis.

Tear film thinning, hyperosmolarity, and breakup can cause irritation and damage to the human eye, and these form an area of active investigation for dry eye syndrome research. Recent research demonstrates that deficiencies in the lipid layer may cause locally increased evaporation, inducing conditions for breakup. In this paper, we explore the conditions for tear film breakup by considering a model for tear film dynamics with two mobile fluid layers, the aqueous and lipid layers. In addition, we include the effects of osmosis, evaporation as modified by the lipid, and the polar portion of the lipid layer. We solve the system numerically for reasonable parameter values and initial conditions and analyze how shifts in these cause changes to the system's dynamics.

Single best answer question-writing tips for clinicians.

Assessment is essential for progression in medical careers. Thus, an important aspect of developing as a clinical teacher is the ability to produce high-quality assessments for junior colleagues. The single best answer (SBA) question format is becoming ubiquitous in the assessment of the application of knowledge in clinical medicine; writing this style of examination question can be a challenge. This concise guide highlights key SBA question-writing tips, aiming to help aspiring clinical teachers set high-quality knowledge assessments.

Shared decision-making in epilepsy management.

Policy makers, clinicians, and patients increasingly recognize the need for greater patient involvement in clinical decision-making. Shared decision-making helps address these concerns by providing a framework for clinicians and patients to make decisions together using the best evidence. Shared decision-making is applicable to situations where several acceptable options exist (clinical equipoise). Such situations occur commonly in epilepsy, for example, in decisions regarding the choice of medication, treatment in pregnancy, and medication withdrawal. A talk model is a way of implementing shared decision-making during consultations, and decision aids are useful tools to assist in the process. Although there is limited evidence available for shared decision-making in epilepsy, there are several benefits of shared decision-making in general including improved decision quality, more informed choices, and better treatment concordance.

Genetic epilepsy with febrile seizures plus: definite and borderline phenotypes.

Generalised epilepsy with febrile seizures plus (GEFS+) is the most studied familial epilepsy syndrome. However, characteristics of UK families have not previously been reported. Among the first 80 families recruited to our families study, four broad subphenotypes were identified: families with classical GEFS+; families with borderline GEFS+; families with unclassified epilepsy; and families with an alternative syndromal diagnosis. Borderline GEFS+ families shared many characteristics of classical GEFS+ families-such as prominent febrile seizures plus and early onset febrile seizures-but included more adults with focal epilepsies (rather than the idiopathic generalised epilepsies predominating in GEFS+) and double the prevalence of migraine. Thus the authors believe that a novel and robust familial epilepsy phenotype has been identified. Subcategorising families with epilepsy is helpful in targeting both clinical and research resources. Most families with GEFS+ have no identified causal mutation, and so predicting genetic homogeneity by identifying endophenotypes becomes more important.

Awake seizures after pure sleep-related epilepsy: a systematic review and implications for driving law.

Who with sleep seizures is safe to drive? Driving law is controversial; ineligibility varies between individual US states and EU countries. Current UK driving law is strongly influenced by a single-centre study from 1974 where most participants were not taking antiepileptic drugs (AEDs). However, pure sleep-related epilepsy is often fully controlled on medication, and its withdrawal can provoke awake seizures. This systematic review asked, 'What is the risk of awake seizures in pure sleep-related epilepsy?' 9885 titles were identified; 2312 were excluded (not human or adult); 40 full texts were reviewed; six papers met our inclusion criteria; each of these six studies had a different pure sleep-related epilepsy definition. Using the largest prospective study, we were able to calculate next year's awake seizure chance (treated with antiepileptic medication). This was maximal in the second year: 5.7% (95% CI 3.0 to 10.4%). European licensing bodies including the UK's Driver and Vehicle Licensing Agency broadly accept a risk of less than 20% for Group 1 licensing. However, this study excluded patients with frontal-lobe epilepsies. Furthermore, follow-up (n=160) varied from 2 to 6 years, yet new awake seizures may occur even after 10-20 years of pure sleep-related epilepsy A paucity of evidence underpins present licensing law; current rulings would be difficult to defend if legally challenged. The law may be penalising people with pure sleep-related epilepsy without increased risk of awake seizures, while failing to identify subgroups at unacceptable risk of an awake seizure at the wheel.

Identifying and prioritising epilepsy treatment uncertainties.

OBJECTIVE: To identify and prioritise uncertainties regarding epilepsy treatment from people with epilepsy, their carers and epilepsy clinicians. BACKGROUND: Failure to acknowledge and address genuine treatment uncertainties has caused unnecessary iatrogenic harm. The authors define an uncertainty as a question that cannot be sufficiently answered by a systematic review of the literature. The database of the uncertainties of the effects of treatment (DUETs) is a collection of 'known unknowns' that enables patient-prioritised research. DESIGN AND PARTICIPANTS: The authors organised five separate focus groups (two consisting of clinicians, three of patients and carers) to garner questions on epilepsy treatment uncertainties; these yielded 398 potential research questions. Participants were asked to rank the questions in terms of importance. The authors then performed a thematic analysis. RESULTS: Patients rated questions concerning cognitive drug side effects, managing the consequences of side effects and improving public awareness about the treatment of epilepsy through improved services as most important. For clinicians, the most important themes were treatment programmes for non-epileptic attack disorder (NEAD), concerns about side effects in utero and uncertainties regarding prescribing in pregnancy. CONCLUSIONS: Patient uncertainties were often focussed on very practical considerations-how to take prescribed medication, access to services and how to minimise drug side effects. Clinicians' questions were also practical but clustered around 'the challenging consultation'-for example, NEAD, sudden unexplained death in epilepsy and prescribing in pregnancy. The authors have published the research questions on NHS Evidence and are working with them to identify those questions which represent genuine uncertainties. The authors encourage other clinicians to seek patient and carers' priorities in order to shape their research agenda.

Kom ombo: preliminary report on the fauna of late paleolithic sites in upper egypt.

A Late Pleistocene fauna comprising 3 fish, 1 reptile, 22 birds, and 14 mammals is identified from sites containing Sebilian, Sebekian, Silsilian, Menchian, and Halfan industries. It is remarkable for its variety, especially of birds, and gives evidence for year-round occupation of these sites.

Research in the prehistory of central Western iran.

The archeological sequence in the Bisitun and Kangovar valleys promises to fill a number of gaps in the prehistory of this part of southwestern Asia. Ghar-i Khar should yield data concerning the degree of cultural continuity or discontinuity in the Upper Pleistocene and early Holocene ranges of prehistory. This cave site should also be helpful in gaining further insight into the climatic conditions during these times, and in particular on the prevalent fauna and flor (and the human use of them) at the close of the Pleistocene, when some groups may already have been leading ways of life foreshadowing the Neolithic. Ganj-i Dareh offers the opportunity of examining in detail what seems to be an early farming community at or very near the beginning of an important shift in methods of subsistence. The geographical position of this latter site may also be of unusual significance in studying the spread of the Neolithic; located as it is near the traditional route across the Zagros Mountains into Iraq, this site, as well as others in the region, may have played an important role in the diffusion of the new elements and methods to other parts of the mountainous zone. That is, within the broad "natural habitat zone" it may be useful to distinguish optimum areas of development and diffusion during the early phases of the Neolithic. Comparison with small sites like Tepe Asiab in the Kermanshah Valley (considered to have been a temporary encampment of clam collectors) (7) may place such sites in their proper perspective as seasonally occupied satellites of more permanent villages such as Ganj-i Dareh; the same possibility is open for the later ceramic Neolithic phase now that the oldest level of Godin Tepe shows a community to which nearby sites on this time horizon can probably be related. However, it will require an intimate study of the two valleys as microenvironments, and comparison of them with each other and with the Kermanshah and Hulailan valleys, in order to reach a fuller understanding of the interrelationships of the various aceramic and ceramic Neolithic sites from the 9th to the 6th millennium. Again, only further exploration in the region will reveal whether the absence of recognizable farming-community sites in the Zagros region during the 8th millennium reflects a genuine hiatus or simply insufficient investigation (21). A broader clearance of Period VII at Godin Tepe itself will enable us better to define the period during which material from Period VII is found stratigraphically associated with later material. Through the horizontal clearance of one of the six small sites in the Kangovar-Bisitun area where similar materials in the pottery Neolithic period are found on or near the surface, by sounding perhaps one other such site, and by plotting all the sites in the region that date to this period, we should be able to reconstruct a reasonably complete picture of this valley at the time of Godin VII. One of these small sites in the neighborhood may yet yield evidence on the relationship between the aceramic and pottery phases of the Neolithic. Godin, of course, provides us an excellent opportunity to examine the relationship between the pottery of the Neolithic and subsequent cultural periods in western Iran, since there appears to be no major break in the developmental sequence between Godin VII and VI. For the periods after the pottery Neolithic in western Iran we have had only the more or less stratified sequence of tombs excavated at Tepe Giyan on which to base our understanding of the developmental sequence from the 6th to the 1st millennium B. C. Even the evidence from our preliminary testing of Godin Tepe indicates how sketchy that understanding has been, since previously we had only suspected the presence of the Uruk culture in the area and had no evidence at all that the culture defined at Yanik Tepe near Tabriz, which has strong links with eastern Anatolia and the Caucasus, ever spread as far south as the central Zagros. Continued research at Godin will shed light on these new problems as well as on many of the long-standing issues that have puzzled archeologists concerned with the Bronze and Iron ages in western Iran.

Mathematical modelling of glob-driven tear film breakup.

Evaporation is a recognized contributor to tear film thinning and tear breakup (TBU). Recently, a different type of TBU is observed, where TBU happens under or around a thick area of lipid within a second after a blink. The thick lipid corresponds to a glob. Evaporation alone is too slow to offer a complete explanation of this breakup. It has been argued that the major reason of this rapid tear film thinning is divergent flow driven by a lower surface tension of the glob (via the Marangoni effect). We examine the glob-driven TBU hypothesis in a 1D streak model and axisymmetric spot model. In the model, the streak or spot glob has a localized high surfactant concentration, which is assumed to lower the tear/air surface tension and also to have a fixed size. Both streak and spot models show that the Marangoni effect can lead to strong tangential flow away from the glob and may cause TBU. The models predict that smaller globs or thinner films will decrease TBU time (TBUT). TBU is located underneath small globs, but may occur outside larger globs. In addition to tangential flow, evaporation can also contribute to TBU. This study provides insights about mechanism of rapid thinning and TBU which occurs very rapidly after a blink and how the properties of the globs affect the TBUT.

Goya's deafness.

Francisco Goya (1746-1828), a major Spanish artist, became profoundly deaf aged 46 years, following an acute illness. Despite this, his success continued and he eventually died aged 82 years. His illness is sketchily documented in letters written during his convalescence, describing headache, deafness, tinnitus, unsteadiness and visual disturbance with recovery (apart from deafness) over three months. There was a milder similar illness two years before, suggesting a relapsing condition. Vogt-Koyanagi-Harada syndrome, although previously accepted as Goya's diagnosis, is not supported by the limited evidence. Susac's syndrome or Cogan's syndrome, although both rare, are more likely explanations.

Computed flow and fluorescence over the ocular surface.

Fluorescein is perhaps the most commonly used substance to visualize tear film thickness and dynamics; better understanding of this process aids understanding of dry eye syndrome which afflicts millions of people. We study a mathematical model for tear film flow, evaporation, solutal transport and fluorescence over the exposed ocular surface during the interblink. Transport of the fluorescein ion by fluid flow in the tear film affects the intensity of fluorescence via changes in concentration and tear film thickness. Evaporation causes increased osmolarity and potential irritation over the ocular surface; it also alters fluorescein concentration and thus fluorescence. Using thinning rates from in vivo measurements together with thin film equations for flow and transport of multiple solutes, we compute dynamic results for tear film quantities of interest. We compare our computed fluorescent intensity distributions with in vivo observations. A number of experimental features are recovered by the model.

Clinical skills evaluation of trainees in a neurology department.

Three to 12 evaluations of clinical performance using the mini-clinical evaluation exercise (Mini-CEX) (n = 124) or direct observation of procedural skills (DOPS) (n = 21) were performed on 27 trainees working in an NHS neurology department. The communications/ counselling skills subdomain was scored in 64 evaluations. For Mini-CEX the focus was on gathering data (22%), diagnosis (31%), management (34%) and counselling (7%) (focus not recorded in 6%). For DOPS, lumbar puncture was the most common evaluated procedure (57%). Mini-CEX evaluations lasted 23.8 minutes (10.6) (mean, sd) and DOPS 25.9 minutes (12.6). Mini-CEX scores for overall competence and communication skills were mean 5.99 (sd 0.95, range 4-8) and 5.98 (sd 1.21, range 3-9) and for DOPS 5.71 (sd 0.90, range 4-8) both on scales of 1 to 9. Overall trainee competence and communication scores increased with year of training (p < 0.001, p < 0.004 univariate analysis). Assessors undertook up to three or four assessments in a session. Assessors and trainees considered that the observation and feedback had been 'very' or 'quite' useful in providing a relevant element of assessment. These assessments were feasible and useful in a neurology department and provided some evidence for increasing performance with trainee seniority. More assessor time (approximately one hour) than trainee time (24-26 min) was needed for each assessment undertaken.

Epilepsy and Pregnancy: For healthy pregnancies and happy outcomes. Suggestions for service improvements from the Multispecialty UK Epilepsy Mortality Group.

Between 2009 and 2012 there were 26 epilepsy-related deaths in the UK of women who were pregnant or in the first post-partum year. The number of pregnancy-related deaths in women with epilepsy (WWE) has been increasing. Expert assessment suggests that most epilepsy-related deaths in pregnancy were preventable and attributable to poor seizure control. While prevention of seizures during pregnancy is important, a balance must be struck between seizure control and the teratogenic potential of antiepileptic drugs (AEDs). A range of professional guidance on the management of epilepsy in pregnancy has previously been issued, but little attention has been paid to how optimal care can be delivered to WWE by a range of healthcare professionals. We summarise the findings of a multidisciplinary meeting with representation from a wide group of professional bodies. This focussed on the implementation of optimal pregnancy epilepsy care aiming to reduce mortality of epilepsy in mothers and reduce morbidity in babies exposed to AEDs in utero. We identify in particular -What stage to intervene - Golden Moments of opportunities for improving outcomes -Which Key Groups have a role in making change -When - 2020 vision of what these improvements aim to achieve. -How to monitor the success in this field We believe that the service improvement ideas developed for the UK may provide a template for similar initiatives in other countries.

Selecting specialist registrars by station interview.

Appointments to the specialist registrar (SpR) grade depend almost entirely on performance at interview, yet standard panel interviews do not directly assess the competences required of a medical trainee. In this study, station interviews were used to select neurology SpRs. Eighteen candidates were assessed in three interviews, each involving three stations: a curriculum vitae (CV)-based interview, an interview with a simulated patient, and a discussion of scenarios based upon teaching, audit and research. Two or three assessors at each station ranked candidates independently before discussing the pooled rankings and reading written references. The CV-based interview rankings (resembling a traditional panel interview) correlated less well with the overall rankings (r=0.54) than did research (r=0.83), information giving (r=0.75), audit (r=0.70) or teaching presentation (r=0.59). Station interviews appear fairer (providing more time, more independent examiners, fresh starts at each station), although they require more planning and expense. Competency-based assessments should be more widely used in selecting medical trainees.

Translational and rotational diffusion of proteins.

We have investigated the translational and rotational diffusion of two proteins, bovine pancreatic trypsin inhibitor and hen egg white lysozyme, using molecular dynamics simulations in explicit solvent. The translational diffusion constants obtained from the simulations compare favourably with results from experiments. However, rotational diffusion constants indicate increased rotational diffusion compared to experiments. Further analysis, using simple hydration models, suggests that the observed rotational diffusion can be explained without invoking a fixed shell of hydration water associated with the protein. Within the assumptions of the hydration models, the results suggest that the strength of protein-water interactions in the current force field may be slightly underestimated.

Internal mobility of the basic pancreatic trypsin inhibitor in solution: a comparison of NMR spin relaxation measurements and molecular dynamics simulations.

Order parameters as well as longitudinal and transverse relaxation rates are calculated for the backbone 15N and 13C alpha nuclei of the basic pancreatic trypsin inhibitor (BPTI) from a 1000 ps molecular dynamics trajectory in explicit water at 277 K using the "model free" approach of Lipari and Szabo. New NMR relaxation data at 277 K are presented, and a comparison is made between NMR relaxation measurements and molecular dynamics relaxation data. It is found that the relaxation processes determining the longitudinal (T1) relaxation rates are inadequately sampled even during this length of simulation. In effect, the calculated relaxation rates are determined almost solely by the order parameters and the overall rotational correlation time of the protein, which appears to be in clear contrast to experimental relaxation rates.

Approach to the patient with epilepsy in the outpatient department.

Epilepsy is common and serious (prevalence 750 per 100 000) and has an impact upon employment, education, and driving. The diagnosis requires a detailed history including witness account. Clinicians must distinguish seizures particularly from syncope and psychogenic attacks. Electroencephalography and magnetic resonance brain scanning help to identify causes and classification of epilepsy, but alone rarely provide the diagnosis. Antiepileptic drug treatment is required long term and is potentially hazardous; patients should start treatment only after informed discussion with an epilepsy specialist. Patients require reliable written information, particularly the driving regulations, and the impact of seizures on employment, education, and leisure. Women must understand the potential drug teratogenic effects. Certain patient groups benefit from targeted epilepsy services, for example, learning disabled, children, teenagers, and elderly. People with epilepsy require long term specialist follow up. Although this is currently provided in mainly in secondary care (including nurse led clinics), improved liaison with primary care should enable improved access to epilepsy services. Epilepsy care should be multidisciplinary and long term, linking primary and secondary care, and empowering patients towards improved management of their condition.

Dynamics and function of the tear film in relation to the blink cycle.

Great strides have recently been made in quantitative measurements of tear film thickness and thinning, mathematical modeling thereof and linking these to sensory perception. This paper summarizes recent progress in these areas and reports on new results. The complete blink cycle is used as a framework that attempts to unify the results that are currently available. Understanding of tear film dynamics is aided by combining information from different imaging methods, including fluorescence, retroillumination and a new high-speed stroboscopic imaging system developed for studying the tear film during the blink cycle. During the downstroke of the blink, lipid is compressed as a thick layer just under the upper lid which is often released as a narrow thick band of lipid at the beginning of the upstroke. "Rippling" of the tear film/air interface due to motion of the tear film over the corneal surface, somewhat like the flow of water in a shallow stream over a rocky streambed, was observed during lid motion and treated theoretically here. New mathematical predictions of tear film osmolarity over the exposed ocular surface and in tear breakup are presented; the latter is closely linked to new in vivo observations. Models include the effects of evaporation, osmotic flow through the cornea and conjunctiva, quenching of fluorescence, tangential flow of aqueous tears and diffusion of tear solutes and fluorescein. These and other combinations of experiment and theory increase our understanding of the fluid dynamics of the tear film and its potential impact on the ocular surface.

Whole mount immunofluorescence analysis of placentas from normotensive versus preeclamptic pregnancies.

INTRODUCTION: Defects in placental angiogenesis and spiral artery remodeling have been proposed to play essential roles in the development of preeclampsia. However, the specific molecular mechanism(s) responsible for aberrant placental angiogenesis in preeclampsia are incompletely understood. The vascular endothelial growth factor receptors (VEGFR1, R2, R3) and STAT3 have critical functions in normal blood vessel development, but their potential roles in preeclampsia are currently unclear. In this study, we utilized a novel whole mount immunofluorescence (WMIF) method to compare expression of VEGFR1, R2, R3 and activated, phosphorylated STAT3 (pSTAT3) in placentas of preeclamptic (PE) versus normotensive (NT) pregnancies. METHODS: Placental biopsies collected from NT and PE pregnant women were fixed and stained with fluorochrome-conjugated antibodies to identify specific cell populations as follows: CD31 for blood vessel endothelial cells, cytokeratin-7 for trophoblast cells, and CD45 for immune cells. Expression of the VEGFRs and pSTAT3 were subsequently characterized by WMIF in conjunction with confocal microscopy. RESULTS: A total of 18 PE and 18 NT placentas were evaluated. No significant differences in the cell type-specific expression patterns or expression levels of VEGFR1, VEGFR2 or VEGFR3 were detected between NT and PE placentas. In contrast, statistically significant increases in pSTAT3 staining were detected in endothelial cells of PE placentas versus NT controls. DISCUSSION: Our study demonstrates that increased pSTAT3 expression in placental endothelial cells is associated with PE. We speculate that elevated pSTAT3 expression in the blood vessels of PE placentas may be due to aberrant angiogenesis, increased pro-inflammatory cytokine expression, and/or placental stress.