EXPERT-SYSTEM SUPPORT USING BAYESIAN BELIEF NETWORKS IN THE DIAGNOSIS OF FINE-NEEDLE ASPIRATION BIOPSY SPECIMENS OF THE BREAST

Aim-To develop an expert system model for the diagnosis of fine needle aspiration cytology (FNAC) of the breast.

Methods-Knowledge and uncertainty were represented in the form of a Bayesian belief network which permitted the combination of diagnostic evidence in a cumulative manner and provided a final probability for the possible diagnostic outcomes. The network comprised 10 cytological features (evidence nodes), each independently linked to the diagnosis (decision node) by a conditional probability matrix. The system was designed to be interactive in that the cytopathologist entered evidence into the network in the form of likelihood ratios for the outcomes at each evidence node.

Results-The efficiency of the network was tested on a series of 40 breast FNAC specimens. The highest diagnostic probability provided by the network agreed with the cytopathologists' diagnosis in 100% of cases for the assessment of discrete, benign, and malignant aspirates. A typical probably benign cases were given probabilities in favour of a benign diagnosis. Suspicious cases tended to have similar probabilities for both diagnostic outcomes and so, correctly, could not be assigned as benign or malignant. A closer examination of cumulative belief graphs for the diagnostic sequence of each case provided insight into the diagnostic process, and quantitative data which improved the identification of suspicious cases.

Conclusion-The further development of such a system will have three important roles in breast cytodiagnosis: (1) to aid the cytologist in making a more consistent and objective diagnosis; (2) to provide a teaching tool on breast cytological diagnosis for the non-expert; and (3) it is the first stage in the development of a system capable of automated diagnosis through the use of expert system machine vision.

Investigation of Genetic Variation in Scavenger Receptor Class B, Member 1 (SCARB1) and Association with Serum Carotenoids

Objective: To investigate association of scavenger receptor class B, member 1 (SCARB1) genetic variants with serum carotenoid levels of lutein (L) and zeaxanthin (Z) and macular pigment optical density (MPOD).
Design: A cross-sectional study of healthy adults aged 20 to 70.
Participants: We recruited 302 participants after local advertisement.
Methods: We measured MPOD by customized heterochromatic flicker photometry. Fasting blood samples were taken for serum L and Z measurement by high-performance liquid chromatography and lipoprotein analysis by spectrophotometric assay. Forty-seven single nucleotide polymorphisms (SNPs) across SCARB1 were genotyped using Sequenom technology. Association analyses were performed using PLINK to compare allele and haplotype means, with adjustment for potential confounding and correction for multiple comparisons by permutation testing. Replication analysis was performed in the TwinsUK and Carotenoids in Age-Related Eye Disease Study (CAREDS) cohorts.
Main Outcome Measures: Odds ratios for MPOD area, serum L and Z concentrations associated with genetic variations in SCARB1 and interactions between SCARB1 and gender.
Results: After multiple regression analysis with adjustment for age, body mass index, gender, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, smoking, and dietary L and Z levels, 5 SNPs were significantly associated with serum L concentration and 1 SNP with MPOD (P<0.01). Only the association between rs11057841 and serum L withstood correction for multiple comparisons by permutation testing (P<0.01) and replicated in the TwinsUK cohort (P = 0.014). Independent replication was also observed in the CAREDS cohort with rs10846744 (P = 2×10-4), an SNP in high linkage disequilibrium with rs11057841 (r2 = 0.93). No interactions by gender were found. Haplotype analysis revealed no stronger association than obtained with single SNP analyses.
Conclusions: Our study has identified association between rs11057841 and serum L concentration (24% increase per T allele) in healthy subjects, independent of potential confounding factors. Our data supports further evaluation of the role for SCARB1 in the transport of macular pigment and the possible modulation of age-related macular degeneration risk through combating the effects of oxidative stress within the retina.
Financial Disclosure(s): Proprietary or commercial disclosures may be found after the references. Ophthalmology 2013;120:1632–1640 © 2013 by the American Academy of Ophthalmology.

Limbal stem cell deficiency:Concept, aetiology, clinical presentation, diagnosis and management

Defects in renewal and repair of ocular surface as a result of limbal stem cell deficiency are now known to cause varying ocular, surface morbidity including persistent photophobia, repeated and persistent surface breakdown and overt conjunctivalisation of the cornea. Ocular conditions with abnormalities of ocular surface repair include pterygium, limbal tumours, aniridia, severe scarring following burns, cicatricial pemphigoid and Stevens-Johnson Syndrome, sequelae of mustard gas exposure and Herpes simplex epithelial disease, radiation keratopathy, contact lens induced keratopathy, neuroparalytic keratitis and drug toxicity. Restoring ocular health in these eyes has traditionally been frustrating. An understanding of these intricate cell renewal and maintenance processes has spurred the evolution in recent years of new treatment methods for several blinding diseases of the anterior segment; many more exciting modalities are in the offing. However, there is inadequate awareness among ophthalmologists about the current principles of management of ocular surface disorders. The purpose of this article is to help elucidate the important principles and current treatment methods relevant to ocular surface disorders.

Corneal Allograft Rejection:Risk Factors, Diagnosis, Prevention, and Treatment

Recent advances in corneal graft technology, including donor tissue retrieval, storage and surgical techniques, have greatly improved the clinical outcome of corneal grafts. Despite these advances, immune mediated corneal graft rejection remains the single most important cause of corneal graft failure. Several host factors have been identified as conferring a "high risk" status to the host. These include: more than two quadrant vascularisation, with associated lymphatics, which augment the afferent and efferent arc of the immune response; herpes simplex keratitis; uveitis; silicone oil keratopathy; previous failed (rejected) grafts; "hot eyes"; young recipient age; and multiple surgical procedures at the time of grafting. Large grafts, by virtue of being closer to the host limbus, with its complement of vessels and antigen-presenting Langerhans cells, also are more susceptible to rejection. The diagnosis of graft rejection is entirely clinical and in its early stages the clinical signs could be subtle. Graft rejection is largely mediated by the major histocompatibility antigens, minor antigens and perhaps blood group ABO antigens and some cornea-specific antigens. Just as rejection is mediated by active immune mediated events, the lack of rejection (tolerance) is also sustained by active immune regulatory mechanisms. The anterior chamber associated immune deviation (ACAID) and probably, conjunctiva associated lymphoid tissue (CALT) induced mucosal tolerance, besides others, play an important role. Although graft rejection can lead to graft failure, most rejections can be readily controlled if appropriate management is commenced at the proper time. Topical steroids are the mainstay of graft rejection management. In the high-risk situations however, systemic steroids, and other immunosuppressive drugs such as cyclosporin and tacrolimus (FK506) are of proven benefit, both for treatment and prevention of rejection.

The accuracy of accredited glaucoma optometrists in the diagnosis and treatment recommendation for glaucoma

Aim: To compare the diagnostic performance of accredited glaucoma optometrists (AGO) for both the diagnosis of glaucoma and the decision to treat with that of routine hospital eye care, against a reference standard of expert opinion (a consultant ophthalmologist with a special interest in glaucoma). Methods: A directly comparative, masked, performance study was undertaken in Grampian, Scotland. Of 165 people invited to participate, 100 (61%) were examined. People suspected of having glaucoma underwent, within one month, a full ophthalmic assessment in both a newly established community optometry led glaucoma management scheme and a consultant led hospital eye service. Results: Agreement between the AGO and the consultant ophthalmologist in diagnosing glaucoma was substantial (89%; ? = 0.703, SE = 0.083). Agreement over the need for treatment was also substantial (88%; ? = 0.716, SE = 0.076). The agreement between the trainee ophthalmologists and the consultant ophthalmologist in the diagnosis of glaucoma and treatment recommendation was moderate (83%, ? = 0.541, SE = 0.098, SE = 0.98; and 81%, ? = 0.553, SE = 0.90, respectively). The diagnostic accuracy of the optometrists in detecting glaucoma in this population was high for specificity (0.93 (95% confidence interval, 0.85 to 0.97)) but lower for sensitivity (0.76 (0.57 to 0.89)). Performance was similar when accuracy was assessed for treatment recommendation (sensitivity 0.73 (0.57 to 0.85); specificity 0.96 (0.88 to 0.99)). The differences in sensitivity and specificity between AGO and junior ophthalmologist were not statistically significant. Conclusions: Community optometrists trained in glaucoma provided satisfactory decisions regarding diagnosis and initiation of treatment for glaucoma. With such additional training in glaucoma, optometrists are at least as accurate as junior ophthalmologists but some cases of glaucoma are missed.

Serum Inflammatory Markers and Preeclampsia in Type 1 Diabetes:A prospective study

OBJECTIVE Inflammation and endothelial dysfunction have been associated with the immunobiology of preeclampsia (PE), a significant cause of adverse pregnancy outcomes. The prevalence of PE is elevated several fold in the presence of maternal type 1 diabetes mellitus (T1DM). Although cross-sectional studies of pregnancies among women without diabetes have shown altered inflammatory markers in the presence of PE, longitudinal studies of diabetic women are lacking. In maternal serum samples, we examined the temporal associations of markers of inflammation with the subsequent development of PE in women with T1DM. RESEARCH DESIGN AND METHODS We conducted longitudinal analyses of serum C-reactive protein (CRP), adhesion molecules, and cytokines during the first (mean ± SD, 12.2 ± 1.9 weeks), second (21.6 ± 1.5 weeks), and third (31.5 ± 1.7 weeks) trimesters of pregnancy (visits 1-3, respectively). All study visits took place before the onset of PE. Covariates were BMI, HbA1c, age of onset, duration of diabetes, and mean arterial pressure. RESULTS In women with T1DM who developed PE versus those who remained normotensive, CRP tended to be higher at visits 1 (P = 0.07) and 2 (P = 0.06) and was significantly higher at visit 3 (P <0.05); soluble E-selectin and interferon-?-inducible protein-10 (IP-10) were significantly higher at visit 3; interleukin-1 receptor antagonist (IL-1ra) and eotaxin were higher and lower, respectively, at visit 2 (all P <0.05). These conclusions persisted following adjustment for covariates. CONCLUSIONS In pregnant women with T1DM, elevated CRP, soluble E-selectin, IL-1ra, and IP-10 and lower eotaxin were associated with subsequent PE. The role of inflammatory factors as markers and potential mechanisms of the high prevalence of PE in T1DM merits further investigation.

The impact of sperm DNA damage in assisted conception and beyond: recent advances in diagnosis and treatment

Abstract Sperm DNA damage is a useful biomarker for male infertility diagnosis and prediction of assisted reproduction outcomes.
It is associated with reduced fertilization rates, embryo quality and pregnancy rates, and higher rates of spontaneous miscarriage
and childhood diseases. This review provides a synopsis of the most recent studies from each of the authors, all of whom have major
track records in the field of sperm DNA damage in the clinical setting. It explores current laboratory tests and the accumulating body
of knowledge concerning the relationship between sperm DNA damage and clinical outcomes. The paper proceeds to discuss the
strengths, weaknesses and clinical applicability of current sperm DNA tests. Next, the biological significance of DNA damage in
the male germ line is considered. Finally, as sperm DNA damage is often the result of oxidative stress in the male reproductive tract,
the potential contribution of antioxidant therapy in the clinical management of this condition is discussed. DNA damage in human spermatozoa is an important attribute of semen quality. It should be part of the clinical work up and properly controlled trials
addressing the effectiveness of antioxidant therapy should be undertaken as a matter of urgency.

Serum carotenoids and fat-soluble vitamins in women with type 1 diabetes and preeclampsia:a longitudinal study

Increased oxidative stress and immune dysfunction are implicated in preeclampsia (PE) and may contribute to the two- to fourfold increase in PE prevalence among women with type 1 diabetes. Prospective measures of fat-soluble vitamins in diabetic pregnancy are therefore of interest.

Increased serum kallistatin levels in type 1 diabetes patients with vascular complications

Kallistatin, a serpin widely produced throughout the body, has vasodilatory, anti-angiogenic, anti-oxidant, and anti-inflammatory effects. Effects of diabetes and its vascular complications on serum kallistatin levels are unknown.

Increased serum pigment epithelium-derived factor is associated with microvascular complications, vascular stiffness and inflammation in Type 1 diabetes

To determine in Type 1 diabetes patients if levels of pigment epithelium-derived factor (PEDF), an anti-angiogenic, anti-inflammatory and antioxidant factor, are increased in individuals with complications and positively related to vascular and renal dysfunction, body mass index, glycated haemoglobin, lipids, inflammation and oxidative stress.

Diabetic retinopathy and serum lipoprotein subclasses in the DCCT/EDIC cohort

To determine associations between retinopathy status and detailed serum lipoprotein subclass profiles in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC) cohort.

Serum lipoproteins in the diabetes control and complications trial/epidemiology of diabetes intervention and complications cohort:associations with gender and glycemia

To relate the nuclear magnetic resonance (NMR)-determined lipoprotein profile, conventional lipid and apolipoprotein measures, and in vitro oxidizibility of LDL with gender and glycemia in type 1 diabetes.

Increased serum pigment epithelium derived factor levels in Type 2 diabetes patients

Serum PEDF levels (mean (S.D.)) were increased in 96 Type 2 diabetic vs. 54 non-diabetic subjects; 5.3 (2.8) vs. 3.2 (2.0)mug/ml, p

A novel single base deletion in the LDLR gene (211delG):Effect on serum lipid profiles and the influence of other genetic polymorphisms in the ACE, APOE and APOB genes

A single base deletion (211delG) in the low density lipoprotein receptor (LDLR) gene was shown to cause familial hypercholesterolaemia (FH) in a large family from Northern Ireland. Twenty-four of 52 family members tested had this mutation, 13 of which were newly diagnosed. Mutation-positive individuals had significantly higher mean total-cholesterol (TC) and LDL-cholesterol (LDL-C) than those without 211delG. LDL-C was a more accurate indicator of disease status than TC, When TC levels alone were considered, in individuals over 16 years, a false negative rate (TC <7.5 mmol/l) of 40% was found; however, this fell to 13% based on inclusion of LDL-C levels. Individuals with coronary artery disease (CAD) had significantly higher TC levels than those without CAD and tended to have tendinous xanthomas (TX) and corneal arcus (CA). Genetic polymorphisms in the angiotensin converting enzyme (ACE) and apolipoprotein (ape) B genes did not appear to be associated with lipid levels or with the clinical severity of the disease; however, the apo E e4 allele did show a lipid-raising effect in individuals with the mutation.

Serum apolipoprotein AI and B are stronger biomarkers of diabetic retinopathy than traditional lipids

OBJECTIVE - To describe and compare the associations of serum lipoproteins and apolipoproteins with diabetic retinopathy. RESEARCH DESIGN AND METHODS - This was a cross-sectional study of 224 diabetic patients (85 type 1 and 139 type 2) froma diabetes clinic. Diabetic retinopathy was graded from fundus photographs according to the Airlie House Classification system and categorized into mild, moderate, and vision-threatening diabetic retinopathy (VTDR). Serum traditional lipids (total, LDL, non-HDL, and HDL cholesterol and triglycerides) and apolipoprotein AI (apoAI), apolipoprotein B (apoB), and the apoB-to-apoAI ratio were assessed. RESULTS - Diabetic retinopathy was present in 133 (59.4%) individuals. After adjustment for age, sex, diabetes duration, A1C, systolic blood pressure, and diabetes medications, the HDL cholesterol level was inversely associated with diabetic retinopathy (odds ratio 0.39 [95% CI 0.16-0.94], highest versus lowest quartile; P = 0.017). The ApoAI level was inversely associated with diabetic retinopathy (per SD increase, 0.76 [95% CI 0.59-0.98]), whereas apoB (per SD increase, 1.31 [1.02-1.68]) and the apoB-to-apoAI ratio (per SD increase, 1.48 [1.13-1.95]) were positively associated with diabetic retinopathy. Results were similar for mild to moderate diabetic retinopathy and VTDR. Traditional lipid levels improved the area under the receiver operating curve by 1.8%, whereas apolipoproteins improved the area by 8.2%. CONCLUSIONS - ApoAI and apoB and the apoB-to-apoAI ratio were significantly and independently associated with diabetic retinopathy and diabetic retinopathy severity and improved the ability to discriminate diabetic retinopathy by 8%. Serum apolipoprotein levels may therefore be stronger biomarkers of diabetic retinopathy than traditional lipid measures. © 2011 by the American Diabetes Association.