Genetic risk for squamous cell carcinoma of the nictitating membrane parallels that of the limbus in Haflinger horses.

Squamous cell carcinoma (SCC) is the most common cancer affecting the equine eye, with a higher incidence documented in Haflinger horses. Recently, a missense variant in the gene damage specific DNA binding protein 2 (DDB2, p.Thr338Met) on ECA12 was identified as a risk factor for the development of limbal SCC in Haflinger horses. SCC also occurs on the nictitating membrane; therefore, investigating the role of this missense variant in nictitating membrane SCC is warranted. In this study, a common ancestor was identified among Haflinger horses affected with limbal SCC or with nictitating membrane SCC, thus supporting a recessive risk factor for the development of cancer at both ocular locations. Analysis of genotype data from Haflinger horses with and without nictitating membrane SCC revealed that the same region on ECA12 associated with limbal SCC was also associated with nictitating membrane SCC (P < 2.04 × 10-5 ). Fine mapping of this locus using 25 cases and 49 controls supported the hypothesis that DDB2:c.1013C>T, p.Thr338Met, is a risk factor for nictitating membrane SCC, as 88% of our cases were homozygous for this variant and no other polymorphism was more strongly associated (P = 4.13 × 10-14 ). These data indicate that the genetic risk is the same for the development of both limbal and nictitating membrane SCC in Haflinger horses and validates utilization of genetic testing of the DDB2 variant for both clinical management and the guidance of mating decisions.

Genetic contribution of CYP1A1 variant on treatment outcome in epilepsy patients: a functional and interethnic perspective.

CYP1A1 gene is involved in estrogen metabolism, and previously, we have reported association of variant rs2606345 with altered anti-epileptic drugs (AED) response in North Indian women with epilepsy (WWE). The present study aims to replicate the pharmacogenetic association, perform functional characterization and study its distribution within ethnically diverse Indian population. The variant was genotyped in 351 patients to assess the pharmacogenetic association and 552 healthy individuals belonging to 24 different ethnic groups to examine the distribution in Indian population. We observed significant overrepresentation of 'A' allele and 'AA' genotype in poor responders in WWE at Bonferroni-corrected significance levels. The recessive allele was found to lower the promoter activity by ~70-80% which was further substantiated by thermally less stable hairpin formed by it (ΔTm=7 °C). Among all ethnic groups, west Indo-European (IE-W-LP2) subpopulation showed highest genotypic frequency of the variant making women from this community more prone to poor AED response. Our results indicate that rs2606345 influences drug response in WWE by lowering CYP1A1 expression.

Surgical learning activities for house officers: do they improve the surgical experience?

OBJECTIVE: To ascertain whether house officers (HOs) attain a more satisfactory surgical rotation experience when they perform basic surgical learning activities. We also sought to establish how many and which learning activities HOs achieve and the effect on their surgical experience. METHODOLOGY: A questionnaire listing 20 learning activities and questions regarding satisfaction with an overall experience was disseminated to HOs in the UK and Ireland who had completed ≥3 months of surgical rotations. Satisfaction with surgical experience was dichotomised in order to perform logistic regression using R Studio software v0.98. RESULTS: The survey was completed by 150 respondents, with 26 % completing at least 10 basic surgical learning activities during their surgical rotation. On multivariate analysis, the completion of these learning activities was significantly associated with a satisfactory rotation experience (p < 0.001). Furthermore, the use of a checklist of surgical activities provided to HOs was associated with a significant increase in the performance of learning activities (p = 0.003). CONCLUSION: Surgical HOs who were informed about potential basic surgical learning activities that can be performed during their rotations performed significantly more of these activities. And these activities were associated with a significantly greater satisfaction with surgical rotations. Therefore, we recommend facilitating HOs completion of these activities as this will ensure that basic surgical competencies are achieved and that HOs will be more satisfied with their surgical experience.

Evidence-based recommendations for negative pressure wound therapy: treatment variables (pressure levels, wound filler and contact layer)--steps towards an international consensus.

Negative pressure wound therapy (NPWT) is becoming a commonplace treatment in many clinical settings. New devices and dressings are being introduced. Despite widespread adoption, there remains uncertainty regarding several aspects of NPWT use. To respond to these gaps, a global expert panel was convened to develop evidence-based recommendations describing the use of NPWT. In a previous communication, we have reviewed the evidence base for the use of NPWT within trauma and reconstructive surgery. In this communication, we present results of the assessment of evidence relating to the different NPWT treatment variables: different wound fillers (principally foam and gauze); when to use a wound contact layer; different pressure settings; and the impact of NPWT on bacterial bioburden. Evidence-based recommendations were obtained by a systematic review of the literature, grading of evidence and drafting of the recommendations by a global expert panel. Evidence and recommendations were graded according to the Scottish Intercollegiate Guidelines Network (SIGN) classification system. In general, there is relatively weak evidence on which to base recommendations for any one NPWT treatment variable over another. Overall, 14 recommendations were developed: five for the choice of wound filler and wound contact layer, four for choice of pressure setting and five for use of NPWT in infected wounds. With respect to bioburden, evidence suggests that reduction of bacteria in wounds is not a major mode of action of NPWT.

Evidence-based recommendations for the use of Negative Pressure Wound Therapy in traumatic wounds and reconstructive surgery: steps towards an international consensus.

Negative pressure wound therapy (NPWT) has become widely adopted over the last 15 years and over 1000 peer reviewed publications are available describing its use. Despite this, there remains uncertainty regarding several aspects of usage. In order to respond to this gap a global expert panel was convened to develop evidence-based recommendations describing the use of NPWT. In this paper the results of the study of evidence in traumatic wounds (including soft tissue defects, open fractures and burns) and reconstructive procedures (including flaps and grafts) are reported. Evidence-based recommendations were obtained by a systematic review of the literature, grading of evidence, drafting of the recommendations by a global expert panel, followed by a formal consultative consensus development program in which 422 independent healthcare professionals were able to agree or disagree with the recommendations. The criteria for agreement were set at 80% approval. Evidence and recommendations were graded according to the SIGN (Scottish Intercollegiate Guidelines Network) classification system. Twelve recommendations were developed in total; 4 for soft tissue trauma and open fracture injuries, 1 for burn injuries, 3 for flaps and 4 for skin grafts. The present evidence base is strongest for the use of NPWT on skin grafts and weakest as a primary treatment for burns. In the consultative process, 11/12 of the proposed recommendations reached the 80% agreement threshold. The development of evidence-based recommendations for NPWT with direct validation from a large group of practicing clinicians offers a broader basis for consensus than work by an expert panel alone.

Medical optimisation can reduce morbidity and mortality associated with elective aortic aneurysm repair.

OBJECTIVES: Patients with aortic aneurysms have significant comorbidities which influence outcome. Our practice includes comprehensive assessment to identify comorbidities, allowing subsequent medical optimisation prior to aneurysm repair. The aim of this study was to assess this process and to identify any factors predictive of outcome. DESIGN: Prospective observational study. MATERIALS: Medical case notes of 200 patients referred with aortic pathology. METHODS: Data analysed included preoperative, perioperative and postoperative factors. Multiple logistic regression analysis was performed to identify predictors of outcome. RESULTS: Following assessment 17 patients (8.5%) were found to be unfit for intervention and 165 patients (82.5%) proceeded to aneurysm repair. In this group assessment uncovered previously undiagnosed cardiac, respiratory and renal comorbidity in 19%, 57% and 29% of patients respectively. Multiple logistic regression analysis indicated that optimisation by a renal physician reduced post-operative renal impairment (OR 0.12, 95% CI 0.03-0.45, P=0.002) while optimisation by a cardiologist reduced respiratory complications (OR 0.7, 95% CI 0.05-0.99, P=0.049). An abnormal echocardiogram was associated with pneumonia (OR 6.9, 95% CI 1.6-29, P=0.01) and death (OR 7.9, 95% CI 1.15-54, P=0.036). CONCLUSION: Pre-operative assessment identifies previously undiagnosed comorbidity in a significant proportion of patients. Subsequent medical optimisation may reduce post-operative morbidity and mortality.

The prevalence of thrombophilia in patients with symptomatic peripheral vascular disease.

BACKGROUND: The aim of this prospective study was to establish the prevalence of thrombophilia and hyperhomocysteinaemia using a comprehensive screen in patients with peripheral vascular disease. METHODS: A total of 150 patients with peripheral vascular disease (with an ankle brachial pressure index of less than 0.8) underwent thrombophilia screening (protein C and protein S, antithrombin, lupus anticoagulant, activated protein C resistance and factor V Leiden and prothrombin mutations). Fasting homocysteine assays were also performed. RESULTS: A thrombophilia defect was found in 41 patients (27.3 per cent). The commonest was protein S deficiency, found in 17 patients (11.3 per cent). Others included factor V Leiden mutation, found in 10 (6.7 per cent) and protein C deficiency, found in six (4.0 per cent). Lupus anticoagulant and prothrombin mutation were both found in six (4.0 per cent). One patient had an antithrombin deficiency. Only the presence of critical ischaemia was associated with a positive thrombophilia screen on single variable analysis (P = 0.03). Hyperhomocysteinaemia was present in over a third of the study group (37.3 per cent): 45 defined as moderate and 11 as intermediate. CONCLUSION: A quarter of patients with peripheral vascular disease had evidence of thrombophilia, and a third had hyperhomocysteinaemia.

Prevalence and risk of thrombophilia defects in vascular patients.

This paper reviews the available data on the prevalence of thrombophilia defects in patients with peripheral vascular disease (PVD) and attempts to delineate the risk of failure of vascular intervention in these patients. The prevalence of thrombophilia in stable claudicants is 25% and increases to 40% in those requiring revascularisation, compared to only 11% in the control group. The overall prevalence of thrombophilia defects in patients with premature atherosclerosis appears to be between 15 and 30%. The prevalence in the typical cohort of patients with PVD appears to be similar. All these studies have recruited patients with symptoms significant enough to warrant intervention. The overall prevalence of thrombophilia calculated from these trials, therefore, may not be truly indicative of the general vascular population who may not even present primary or secondary healthcare. The risk of thrombotic occlusion following arterial revascularisation in patients with an identified thrombophilia defect appears to be almost three times that of patients with no evidence of a thrombophilia defect. The best management of these patients has not been determined and needs to be evaluated by prospective randomized trials.

Thromboelastography: a reliable test?

The thromboelastograph (TEG), a measure of global haemostasis, is routinely used during cardiac and hepatic surgery to optimize blood product selection and usage. It has recently been suggested that it may also be a useful tool to screen patients with hypercoagulable states. Limited published data on performance characteristics has led to speculation regarding its consistency and, therefore, validity of the results. This study was designed to assess the effect of stability of blood samples prior to testing, repeated sampling, intra- and inter-assay variability using the native, celite, tissue factor (TF) and Reopro-modified TEG. Analysis of native and celite samples after storage over 90 min showed a period of instability up to 30 min. Thereafter, all parameters between 30 and 90 min were stable [P = not significant (NS)]. When the same sample was repeatedly assayed, both native and celite TEG parameters showed a significant change towards hypercoagulability (P < 0.01), whereas the TF and Reopro-modified TEG showed no change. Intra- and inter-assay variability on samples tested after 30 min showed excellent reproducibility for all parameters (P = NS). The data suggest that the TEG is a useful tool in haemostasis but requires a formal standard operating procedure to be adopted that takes into account the initial period of sample instability.

Lessons to be learned: a case study approach insulinoma presenting as a change in personality.

A 43-year-old man presented with attacks of altered behaviour over a short period of time; they were associated with episodes of hypoglycaemia. The clinical suspicion of insulinoma prompted investigations that quickly established serum insulin and C-peptide levels to be elevated at the times when blood glucose values were low. A physical lesion was found in the head of the pancreas by means of computerised tomography and endo-duodenal ultrasound scan; an octreotide scan was negative. The patient underwent laparotomy and enucleation of a benign tumour, measuring 2.6 cm in diameter, lying within the head of the pancreas; histological examination confirmed it to be an insulinoma. Postoperatively, the patient's personality gradually became more normal and his fasting blood glucose concentrations returned to within normal limits. The diagnosis and management of insulinoma are discussed in the context of this clinical case; there is also reference to the protean clinical manifestations that may occur in this condition- and its differential diagnosis.

Thromboelastography.

The Thromboelastograph has now been in use for over 50 years and has been largely regarded as a research tool. Increasing automation and refinement of the TEG and standardisation of results has led to decreased speculation regarding its validity as an assay of haemostasis. There are increasing clinical applications including cardiothoracic surgery and liver transplantation. This review discusses the principles and limitations of the TEG. It also focuses on the current clinical applications and potential research interests.

Herbal medicines: current trends in anesthesiology practice--a hospital survey.

STUDY OBJECTIVES: To develop a simple survey to determine the patient population actively utilizing dietary supplements and/or herbs, during the preoperative period. DESIGN: Prospective study, with survey instrument. SETTING: University medical center. PATIENTS: 1,017 patients presenting for preanesthetic evaluation prior to outpatient surgery. INTERVENTIONS: After undergoing preanesthetic evaluation, patients were asked to complete a survey listing which of the nine most popular nutraceuticals currently available on the market they were using. MEASUREMENTS AND MAIN RESULTS: A total of 1017 surveys were submitted over a period of five months, with 32% being poorly completed and thus discarded. Of the remaining 755 valid surveys, 482 patients used at least one nutraceutical agent. 90% of these patients were using vitamins, 43% garlic extracts, 32% Gingko Biloba, 30% St. John's Wort, 18% Ma Huang, 12% Ecchinaceae, 10% Aloe, 8% Cascare, 3% licorice. CONCLUSION: A significant population of patients scheduled for an elective surgical procedure are self-administering nutraceutical agents. Some of these agents have the potential to cause serious drug interactions and hemodynamic instability during surgery. Hence, it may be important to identify patients self-administering these medications, during the preoperative period.

Intermittent claudication: a condition with underrated risks.

Intermittent claudication (IC) is a symptom of peripheral arterial occlusive disease (PAOD); it is subjective and therefore difficult to measure reliably. Both the WHO/Rose Questionnaire and the Edinburgh Questionnaire have been used widely, but they have a low sensitivity and therefore underestimate the true prevalence of IC. The addition of a clinical examination does not necessarily eliminate errors found on questionnaires alone. The single most important part of the physical examination to confirm a diagnosis of IC is the palpation of the patient's peripheral pulses, which alone appears to be more sensitive, but less specific, than the questionnaires. The most useful noninvasive test is the ankle-brachial pressure index (ABPI), and it has been suggested that a resting ABPI of 0.9 is up to 95% sensitive in detecting angiogram-positive disease, and almost 100% specific in identifying apparently healthy individuals. An ABPI of 0.9 or less is believed to be associated with 50% or greater vessel stenosis. The incidence of IC varies depending on the methodology used to define it, but there is a general pattern of a gradual increase in incidence up to the age of at least 70 years. For a chronic disease, the prevalence is a more relevant indicator of how common it is. The prevalence of IC is 3% to 6% in men aged 60 years and increases with age. The prevalence of asymptomatic PAOD may be as high as 20% in the adult population, using noninvasive testing. This is important because, as will be seen in later articles, PAOD, whether symptomatic or asymptomatic, is a serious risk factor for cardiovascular morbidity and mortality.

Predictors of early disease in the lower limbs.

Increasing age and male gender are unavoidable risk factors for peripheral arterial occlusive disease (PAOD). A number of studies have looked at classical risk factors for atherosclerosis, such as diabetes, hypertension, lipid abnormalities, and smoking, as well as some more recently identified associations, such as plasma fibrinogen levels, impaired glucose tolerance, and hyperhomocysteinemia. However, most "risk factors" are really associations. A causal relationship may only reasonably be firmly established if a prospective controlled study shows that removing the risk factor significantly alters the course of the disease, as with smoking. Smoking is probably the strongest risk factor for intermittent claudication (IC), but hyperhomocysteinemia also appears to be strongly associated with the development of PAOD. Moderate alcohol intake and regular physical exercise appear to have a protective effect. A genetic risk factor is suggested but not as yet confirmed. The magnitude of the association varies from odds ratios of 2 to 3 for smoking and diabetes. There is insufficient evidence for hyperhomocysteinemia, but the effect may be even greater. The association with hypertension and lipid abnormalities is surprisingly inconclusive.

Lower-extremity arteriosclerosis as a reflection of a systemic process: implications for concomitant coronary and carotid disease.

Peripheral arterial occlusive disease (PAOD), coronary artery disease (CAD), and cerebrovascular disease (CVD) are all manifestations of atherosclerosis or atherothrombosis, and therefore it is not surprising that the three conditions commonly occur together. Knowledge of the magnitude of co-existing cardiovascular disease and its prognosis is essential for the physician treating IC so that he can treat the local disease in its systemic context. The prevalence of CAD in patients with IC is 40% to 60%, although this may be asymptomatic and increases with the severity of the PAOD. Not surprisingly, the converse is also true; among individuals with CAD, the prevalence of PAOD is higher than in non-CAD individuals. The link between PAOD and CVD seems to be weaker than that with CAD, but again up to 60% of claudicants have some evidence of CVD. The prevalence of patients with CVD increases as the ABPI decreases. The evidence available from all of the relevant studies suggests that approximately 60% of patients with PAOD will have significant disease in the cardiac or cerebral circulation, and approximately 40% of patients with coronary disease or significant cerebral circulatory disease also will have PAOD.

The natural history of claudication: risk to life and limb.

Although a patient with intermittent claudication (IC) will fear progression to severe disease and amputation, this is a relatively rare outcome of claudication, with only 1% to 3% of claudicants ever requiring major amputation over a 5-year period. Indeed, in one study, 50% of claudicants became symptom free during 5 years' follow-up. All the new evidence over the last 40 years has not altered the impression that only about one fourth of patients with IC will ever significantly deteriorate, and that deterioration is most frequent during the first year after diagnosis (6 to 9%) compared with 2% to 3% per annum thereafter. Smoking is the most important risk factor for the progression of local disease in the legs, with an amputation rate 11 times greater in smokers than nonsmokers. Diabetes, male gender, and hypertension are also important risk factors for progression. Because cerebrovascular disease (CVD), coronary artery disease (CAD), and peripheral arterial occlusive disease (PAOD) coexist, PAOD and IC should be regarded as a marker for increased risk from fatal and nonfatal cardiovascular event, and 2% to 4% of claudicants have a nonfatal cardiovascular event every year. The risk is higher in the first year after developing IC than in a long-standing stable claudicant, and the average claudicant is more likely to have a nonfatal myocardial infarction (MI) or stroke in the next year that of ever requiring a major amputation for his leg ischemia. The mortality in claudicants is 30% at 5 years, 50% at 10 years, and 70% at 15 years, without any clear decrease in these figures over the last 30 to 40 years. The mortality of claudicants is approximately two and a half times that of an age-matched general population.