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Quite often patients present at the clinic or surgery complaining of watering eyes. It may be the golfer whose glasses keep misting up on the fairways or the housewife who is embarrassed by tears dropping onto the food when cooking, or it may be the 6-month-old baby whose eyes have watered and discharged since birth. Sometimes an elderly patient may complain of watering eyes when on examination there is no evidence of tear overflow but the vision has been made blurred by cataracts. Some degree of tear overflow is quite normal in windy weather, and the anxious patient may over-emphasise this; it is important to assess the actual amount of overflow by asking the patient whether it occurs all the time both in and out of doors.

Diabetes mellitus is an important cause of blindness: about 1000 people are registered blind from diabetes per year in the United Kingdom. Most of these patients are elderly, but diabetes is the commonest cause of blindness in young people in this country. The management of diabetic eye disease has improved greatly over the past 10 years so that much of this blindness can now be prevented. In spite of this, most general practitioners are aware of tragic cases of rapidly progressive blindness in young diabetics. The more serious manifestations of diabetes in the eye tend to affect patients in the prime of life. The tragedy is even greater when one considers that this blindness is largely avoidable.

This chapter describes the anatomy of the eyeball, the visual pathway, and the ocular adnexae. It also provides a basic introduction to the physiology and functioning of the eye.

This is common and tends to occur spontaneously or sometimes after straining or, especially, vomiting. The eye becomes suddenly red and although the patient may experience a slight pricking, the condition is usually first noticed in the mirror or by a friend. The haemorrhage gradually absorbs in about ten days and investigations usually fail to reveal any underlying cause. Very rarely, it is necessary to cauterise the site of bleeding if the haemorrhage is repeated so often that it becomes a nuisance to the patient (Fig. 5.1).

Background: Personal continuous glucose monitoring (CGM) is patient owned and often inaccessible due to cost and insurance requirements. Professional CGM is clinic owned, worn for 3-14 days and is an affordable, underutilized option. The present study combined diabetes education and professional CGM into a shared medical appointment (SMA). The SMA allows providers to deliver diabetes education in the setting of medical management and peer support. It was hypothesized that the SMA method of delivering professional CGM would positively impact clinical outcomes (improvements in self-efficacy, A1c and medication doses). Methods: Adults with type 1 and type 2 diabetes who attended the two-part CGM SMA at a large academic medical center were included in this retrospective, single-center study. The CGM SMA included 4-6 patients, diabetes educator and pharmacist. Participants wore professional CGM for 7 days. The primary outcome was change in diabetes self-efficacy through a validated 8-item Likert scale. Secondary objectives were changes in A1c, and changes in diabetes medications (dosage adjustments, time of administration). Paired t-tests were used to analyze change in A1c and diabetes self-efficacy scores. Results: Diabetes self-efficacy scores increased by a mean of 1.63 ± 2.09 points (p 8.0% (n=101). Participants utilizing the real time device (n=133) experienced a decrease in A1c by 0.75% compared to 1.0% in those with the blinded device (n=38). Most medication changes made in the CGM SMA were dosage adjustments and changes in administration time. Discussion: The CGM SMA is a novel practice model incorporating diabetes education, peer support, professional CGM, and inter-professional care that demonstrated improvements in diabetes self-efficacy and A1c. Disclosure D. Isaacs: Consultant; Self; Companion Medical, LifeScan, Inc. Speaker’s Bureau; Self; Dexcom, Inc., Novo Nordisk Inc., Xeris Pharmaceuticals, Inc. A. Simonyan: None. J.E. Blanchette: Other Relationship; Self; Tandem Diabetes Care. S. Lekic: None. D. Noe: Consultant; Self; Pyure Organic Stevia. N.R. Galloway: None.

Introduction: Continuous glucose monitoring (CGM) measures glucose up to 288 times per day allowing people with diabetes (PWD) to see in real-time how medications, food, exercise, and stress, affect glucose levels. Clinicians interpret this information to make lifestyle and medication recommendations. Objective: To identify common learning outcomes and planned self-management changes resulting from CGM shared medical appointments. Study Design: A two-part CGM Shared Medical Appointment was led by certified diabetes educators (pharmacists, nurses and dieticians). Professional CGM devices were inserted and participants returned the following week for removal, discussion and education in a group format. Inclusion criteria for this study were as follows: age > 18 years, >3 days of CGM data, and attendance of both classes. A post-course survey was given with structured interview questions asking (1) “What is one thing you learned from the CGM class experience?” and (2) “Which changes do you plan to make to your diabetes care?” Questions were answered in written format. After digital transcription entry, data were coded and analyzed using content analysis to devise themes by two reviewers. Findings: A total of 170 PWD participated in the CGM class and 140 (82.35%) completed the post-course survey. Class sizes ranged from 3-6 participants. The most common learning outcomes were nutrition self-management knowledge (35.77%), pattern interpretation (18.25%) and blood glucose awareness (13.87%). The most common planned self-management changes were nutrition related (56.82%), self-management behavioral goals (24.42%) (log patterns, increase monitoring frequency) and medication adjustments (23.48%) (basal rates, carbohydrate ratios, timing and consistency of medications). Conclusion: Continuous Glucose Monitoring Shared Medical Appointments are an innovative strategy to facilitate lifestyle changes and medication adjustments for people with diabetes. Disclosure J.E. Blanchette: Consultant; Self; Dexcom, Inc., Tandem Diabetes Care. D. Noe: None. N. Galloway: None. H. Sullivan: None. A. Ha: Consultant; Self; Tandem Diabetes Care. D. Isaacs: Advisory Panel; Self; BD, Sanofi-Aventis.

Despite significant clinical and basic science advancements, cancer remains a devastating disease that affects people of all ages, races, and backgrounds. The pathogenesis of cancer has recently been described to result from eight biological capabilities or hallmarks and two enabling characteristics. These eight hallmarks are: deregulation of cellular energetics, avoiding immune destruction, enabling replicative immortality, inducing angiogenesis, sustaining proliferative signaling, evading growth suppressors, resisting cell death, and activating invasion and metastasis. The enabling characteristics are: genome instability and mutation and tumor-promoting inflammation. Survivin, the fourth most common transcript found in cancer cells, is a protein that is thought to be involved in the enhanced proliferation, survival, and metastasis and possibly other key hallmarks of cancer cells. Understanding how this gene is turned on and off is vitally important for attempt improving cancer management and therapy. Our work has identified a novel transcriptional regulator of survivin called Yin Yang 1 (YY1), which has been observed to activate some gene promoters and repress others and is gaining increasing interest as a target of cancer therapy. Our work shows for the first time that YY1 represses survivin transcription by physically interacting with the survivin promoter. Furthermore, YY1 appears to contribute to basal survivin transcriptional activity, indicating that disruption of its binding may in part contribute to survivin overexpression after cellular stress events including chemotherapy and radiotherapy.

The mechanisms for regulation of the Inhibitor of Apoptosis (IAP) Survivin in cells undergoing stress associated with tumor development and the tumor microenvironment are not well understood. The stress response transcription factors HIF-1α and Yin Yang 1 (YY1) were hypothesized to contribute to the upregulation of Survivin in tumor cells. As expected, U2OS cells overexpressing HIF-1α showed a 2- to 3-fold transactivation when transfected. Surprisingly, when YY1 was overexpressed in this survivin promoter reporter system, luciferase expression was repressed 30- to 40-fold. YY1 involvement in survivin promoter repression was confirmed using siRNA directed against YY1. These studies showed that knockdown of YY1 releases the survivin promoter from the observed repression and leads to a 3- to 5-fold increase in promoter activity above basal levels. A U2OS cell line containing a stable YY1 Tet-off system was used to determine whether a temporal increase in YY1 expression affects Survivin protein levels. A low to moderate decrease in Survivin protein was observed 24 h and 48 h after Tet removal. Studies also confirmed that YY1 is capable of directly binding to the survivin promoter. Collectively, these findings identify novel basal transcriptional requirements of survivin gene expression which are likely to play important roles in the development of cancer and resistance to its treatment.

IL-7 is critical for B cell production in adult mice; however, its role in human B lymphopoiesis is controversial. One challenge was the inability to differentiate human cord blood (CB) or adult bone marrow (BM) hematopoietic stem cells (HSCs) without murine stroma. Here, we examine the role of IL-7 in human B cell development using a novel, human-only model based on coculturing human HSCs on primary human BM stroma. In this model, IL-7 increases human B cell production by >60-fold from both CB and adult BM HSCs. IL-7-induced increases are dose-dependent and specific to CD19+ cells. STAT5 phosphorylation and expression of the Ki-67 proliferation Ag indicate that IL-7 acts directly on CD19+ cells to increase proliferation at the CD34+ and CD34− pro-B cell stages. Without IL-7, HSCs in CB, but not BM, give rise to a small but consistent population of CD19lo B lineage cells that express EBF (early B cell factor) and PAX-5 and respond to subsequent IL-7 stimulation. Flt3 ligand, but not thymic stromal-derived lymhopoietin (TSLP), was required for the IL-7-independent production of human B lineage cells. As compared with CB, adult BM shows a reduction of in vitro generative capacity that is progressively more profound in developmentally sequential populations, resulting in an ∼50-fold reduction in IL-7-dependent B lineage generative capacity. These data provide evidence that IL-7 is essential for human B cell production from adult BM and that IL-7-induced expansion of the pro-B compartment is increasingly critical for human B cell production during the progression of ontogeny.

Diffusion-weighted imaging (DWI) and consequent apparent diffusion coefficient (ADC) maps have been used for lesion detection and as a predictor of outcome in adults with traumatic brain injury (TBI), but few studies have been reported in children. We evaluated the role of DWI and ADC for outcome prediction after pediatric TBI (n=37 TBI; n=10 controls). Fifteen regions of interest (ROIs) were manually drawn on ADC maps that were grouped for analysis into peripheral gray matter, peripheral white matter, deep gray and white matter, and posterior fossa. All ROIs excluded areas that appeared abnormal on T2-weighted images (T2WI). Acute injury severity was measured using the Glasgow Coma Scale (GCS) score, and 6-12-month outcomes were assessed using the Pediatric Cerebral Performance Category Scale (PCPCS) score. Patients were categorized into five groups: (1) controls; (2) all TBI patients; (3) mild/moderate TBI with good outcomes; (4) severe TBI with good outcomes; and (5) severe TBI with poor outcomes. ADC values in the peripheral white matter were significantly reduced in children with severe TBI with poor outcomes (72.8+/-14.4x10(-3) mm2/sec) compared to those with severe TBI and good outcomes (82.5+/-3.8x10(-3) mm2/sec; p

Those who regard science as the study of more and more about less and less will find that medicine is no exception to this process of specialisation. It is mainly by the intensive study of minutiae that studies can become effective and lead to the prevention and cure of disease. The eye and its surrounding structures provide us with an ideal terrain for this type of specialisation. The importance of the eye and its function in our daily lives is sometimes underrated, but a consideration of the part played by vision in our consciousness soon makes us realise the value of vision. If we think of dreams, memories, of photographs and of almost anything in our daily existence, it is difficult to express them without visual references. After a little careful consideration of the meaning of blindness, it is easy to sense the rational and irrational fears that our patients present in daily life. In a modern European community the effects of blindness are not so apparent as in former years, and blind people tapping their way around streets or begging for food are less in evidence to remind us of the deprivation which they suffer. This is due to the effective application of preventive medicine and to the efficacy of modern surgical techniques.

Many types of eye disease are inherited and it is always important to enquire about the family history when interviewing a patient with ophthalmological complaints. Some types of inherited eye disease lead to blindness and relatives of patients with such conditions often seek advice concerning their risk of contracting the disease.

Measurement of visual acuity is the most important test of vision performed by the doctor and yet it is surprising how often it is omitted in examination by the non-specialist. It has already been shown that the differential diagnosis of the red eye can be simplified by noting the vision in the affected eye. After injuries of the eye it is just as important to note the vision in the uninjured eye as it is to note that in the injured eye. Simple measurement of the visual acuity is, of course, of limited value without a knowledge of the spectacle correction or whether the patient is wearing the appropriate spectacles.

In this chapter the more important ocular tumours will be considered. There are a considerable number of other rare tumours and the interested student should refer to one of the more specialised and comprehensive textbooks of ophthalmology for further reading.

Fortunately, because they are absorbed through the cornea, it is possible to achieve a high concentration of most drugs in the eye by applying them in the form of eyedrops. In this way a high local concentration can be obtained with minimal risk of systemic side-effects. Certain drugs may produce systemic side-effects, for example the slowing of the pulse after the use of timolol drops or sweating and nausea after frequent use of pilocarpine. The action of local applications may be prolonged by incorporating them in an ointment or, more effectively, by the use of a plastic slow-release device which can be lodged under the upper lid (for example the Ocusert). For most purposes, eyedrops are prescribed in 10-ml amounts in a multiple-dose container. After the container has been opened it should not be kept for longer than a month. In order to avoid undue stinging, drops may be buffered to near the pH of tears and they contain a preservative such as phenyl mercuric nitrate or benzalkonium chloride. It must be borne in mind that patients who develop an allergic reaction to drops may be reacting to the preservative. Single-application containers are also available and these may not contain preservative.

Redness of the eye is one of the commonest signs in ophthalmology, being a feature of a wide range of ophthalmological conditions, some of which are severe and sight threatening whereas some are mild and of little consequence. Occasionally the red eye may be the first sign of important systemic disease. It is important that any practising doctor has an understanding of the differential diagnosis of this common sign, and a categorisation of the signs, symptoms and management of the red eye will now be made from the standpoint of the non-specialist general practitioner.

When the patient with an ophthalmological problem first enters the doctor’s surgery, it is useful to notice whether he or she is long sighted or short sighted. The long-sighted person tends to have smaller eyes than normal, whereas the short-sighted person tends to have larger eyes than normal. Sometimes this is evident on inspection of the eyes and eyelids, but the long-sighted person will usually be wearing convex or converging lenses and these tend to make the eyes look bigger, whereas the short-sighted person will be wearing concave lenses which make the eyes look smaller (Fig. 3.1).

The eye and its supporting structures undergo well known changes with age. As the population continues to age, it is important to distinguish ‘normal’ involutional changes from aging pathology of these structures. This chapter describes the standard age changes, as well as diseases that occur in the eye and its adnexae with age. These include cataracts, age-related macular degeneration, glaucoma and giant cell (or temporal) arteritis.

This chapter describes how to take an ophthalmological history and examine the eye. Various special instruments and techniques which are used in the eye department are described.

OBJECTIVES This study evaluates the efficacy of combining proton irradiation with gemcitabine, and the role the inhibitor of apoptosis proteins survivin and X-linked inhibitor of apoptosis protein (XIAP) play in the radiosensitive versus radioresistant status of pancreatic cancer. METHODS The radioresistant (PANC-1) and radiosensitive (MIA PaCa-2) pancreatic carcinoma cells' response to combined gemcitabine and proton irradiation was compared. Cells were treated with 0.1 to 500 microM gemcitabine and 0- to 15-Gy proton irradiation after which trypan blue and flow cytometry were used to determine changes in the cell cycle and apoptosis. Expression levels of survivin and XIAP were measured using Western blotting. Combination therapy with gemcitabine for 24 hours followed by 10-Gy proton irradiation proved most effective. RESULTS Gemcitabine and proton irradiation resulted in increased survivin levels with little apoptosis. However, combination therapy resulted in robust apoptotic induction with a concomitant survivin and XIAP reduction in the MIA PaCa-2 cells with little effect in the PANC-1 cells. Small interfering RNA studies confirmed a role for XIAP in the radioresistance of PANC-1 cells. CONCLUSIONS Our data demonstrate that combining gemcitabine and proton irradiation enhances apoptosis in human pancreatic cancer cells when XIAP levels decrease. Therefore, XIAP may play an important role in human pancreatic cancer proton radioresistance.

Apparent diffusion coefficient maps from diffusion-weighted imaging predict gross neurologic outcome in adults with traumatic brain injury. Few studies in children have been reported, and none have used apparent diffusion coefficient maps to predict long-term (>1 year) neurocognitive outcomes. In this study, pooled regional and total brain diffusion coefficients were used to predict long-term outcomes in 17 pediatric brain injury patients. Apparent diffusion coefficient values were grouped into peripheral and deep gray and white matter, posterior fossa, and total brain. Regions of interest excluded areas that appeared abnormal on T 2 -weighted images. Apparent diffusion coefficient values from peripheral regions were inversely correlated with cognitive functioning. No significant correlations were apparent between the cognitive scores and apparent diffusion coefficient values for deep tissue or the posterior fossa. Regression analyses suggested that combined peripheral gray and white matter apparent diffusion coefficients explained 42% of the variance in the combined neurocognitive index. Peripheral gray diffusion coefficients alone explained an additional 20% of variance after accounting for clinical variables. These results suggest that obtaining apparent diffusion coefficient values, specifically from peripheral brain regions, may predict long-term outcome after pediatric brain injury. Discrepancies in the literature on this topic, as well as possible explanations, including sampling and clinical considerations, are discussed.

Magnetic resonance imaging (MRI) is increasingly used in the assessment of the severity and progression of neurotrauma. We evaluated temporal and regional changes after mild fluid percussion (FPI) and controlled cortical impact (CCI) injury using T2-weighted-imaging (T2WI) and diffusion-weighted imaging (DWI) MRI over 7 days. Region of interest analysis of brain areas distant to the injury site (such as the hippocampus, retrosplenial and piriform cortices, and the thalamus) was undertaken. In the hippocampus of CCI animals, we found a slow increase (51%) in apparent diffusion coefficients (ADC) over 72 h, which returned to control values. The hippocampal T2 values in the CCI animals were elevated by 18% over the 7-day time course compared to control, indicative of edema formation. Histological analysis supported the lack of overt cellular loss in most brain regions after mild CCI injury. FPI animals showed a generalized decrease in hippocampal ADC values over the first 72 h, which then returned to sham levels, with decreased T2 values over the same period, which remained depressed at 7 days. Histological assessment of FPI animals revealed numerous shrunken cells in the hippocampus and thalamus, but other regions showed little damage. Increased immunohistochemical staining for microglia and astroglia at 7 days post-injury was greater in FPI animals within the affected brain regions. In summary, traumatic brain injury is less severe in mild CCI than FPI, based on the temporal events assessed with MRI.