Do advanced glycation end products contribute to food allergy?

Sugars can bind non-enzymatically to proteins, nucleic acids or lipids and form compounds called Advanced Glycation End Products (AGEs). Although AGEs can form in vivo, factors in the Western diet such as high amounts of added sugars, processing methods such as dehydration of proteins, high temperature sterilisation to extend shelf life, and cooking methods such as frying and microwaving (and reheating), can lead to inordinate levels of dietary AGEs. Dietary AGEs (dAGEs) have the capacity to bind to the Receptor for Advanced Glycation End Products (RAGE) which is part of the endogenous threat detection network. There are persuasive epidemiological and biochemical arguments that correlate the rise in food allergy in several Western countries with increases in dAGEs. The increased consumption of dAGEs is enmeshed in current theories of the aetiology of food allergy which will be discussed.

Dictyostelium, a microbial model for brain disease.

BACKGROUND: Most neurodegenerative diseases are associated with mitochondrial dysfunction. In humans, mutations in mitochondrial genes result in a range of phenotypic outcomes which do not correlate well with the underlying genetic cause. Other neurodegenerative diseases are caused by mutations that affect the function and trafficking of lysosomes, endosomes and autophagosomes. Many of the complexities of these human diseases can be avoided by studying them in the simple eukaryotic model Dictyostelium discoideum. SCOPE OF REVIEW: This review describes research using Dictyostelium to study cytopathological pathways underlying a variety of neurodegenerative diseases including mitochondrial, lysosomal and vesicle trafficking disorders. MAJOR CONCLUSIONS: Generalised mitochondrial respiratory deficiencies in Dictyostelium produce a consistent pattern of defective phenotypes that are caused by chronic activation of a cellular energy sensor AMPK (AMP-activated protein kinase) and not ATP deficiency per se. Surprisingly, when individual subunits of Complex I are knocked out, both AMPK-dependent and AMPK-independent, subunit-specific phenotypes are observed. Many nonmitochondrial proteins associated with neurological disorders have homologues in Dictyostelium and are associated with the function and trafficking of lysosomes and endosomes. Conversely, some genes associated with neurodegenerative disorders do not have homologues in Dictyostelium and this provides a unique avenue for studying these mutated proteins in the absence of endogeneous protein. GENERAL SIGNIFICANCE: Using the Dictyostelium model we have gained insights into the sublethal cytopathological pathways whose dysregulation contributes to phenotypic outcomes in neurodegenerative disease. This work is beginning to distinguish correlation, cause and effect in the complex network of cross talk between the various organelles involved. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research.

Mitral valve repair for ischemic mitral regurgitation: review of current techniques.

INTRODUCTION: Ischemic mitral regurgitation can be defined as moderate to severe mitral leak precipitated by acute myocardial infarction. Valve repair is now the procedure of choice, but some cases can pose difficult anatomy. This review will illustrate current techniques for repairing complex ischemic mitral regurgitation. METHODS: Most patients with ischemic mitral regurgitation have predominant annular dilatation at the posterior commissure and require only ring annuloplasty. Full rigid rings are used preferentially. With leaflet tethering, adjunctive autologous pericardial patches are effective in restoring leaflet coaptation. If papillary muscle elongation or rupture occurs, Gore-Tex artificial chordal replacement performs well. With ischemic mitral regurgitation accompanying posterior ventricular aneurysms, standard trans-atrial mitral repair provides the best results, with associated aneurysms being repaired concurrently. RESULTS: Surgical approaches and technical outcomes of mitral repair in ischemic mitral regurgitation are illustrated in 5 patients using operative images and echocardiograms. Each method is illustrated, including ring annuloplasty, pericardial leaflet augmentation, artificial chordal replacement, and ventricular aneurysm repair. Using these techniques, virtually all ischemic mitral regurgitation can be repaired, with consequential patient benefits, even in the most complex anatomy. CONCLUSIONS: Ischemic mitral regurgitation has been shown to have better outcomes when managed with valve repair. Using combinations of annular, leaflet, and chordal procedures, even complex ischemic mitral regurgitation can undergo autologous reconstruction with excellent long-term results.

Dichotomy of food and inhalant allergen sensitization in eosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EE) is an emerging condition where patients commonly present with symptoms of gastroesophageal reflux disease and fail to respond adequately to anti-reflux therapy. Food allergy is currently recognized as the main immunological cause of EE; recent evidence suggests an etiological role for inhalant allergens. The presence of EE appears to be associated with other atopic illnesses. OBJECTIVES: To report the sensitization profile of both food and inhalant allergens in our EE patient cohort in relation to age, and to profile the prevalence of other allergic conditions in patients with EE. METHOD: The study prospectively analyzed allergen sensitization profiles using skin prick tests to common food allergens and inhalant allergens in 45 children with EE. Patch testing to common food allergens was performed on 33 patients in the same cohort. Comorbidity of atopic eczema, asthma, allergic rhinitis and anaphylaxis were obtained from patient history. RESULTS: Younger patients with EE showed more IgE and patch sensitization to foods while older patients showed greater IgE sensitization to inhalant allergens. The prevalence of atopic eczema, allergic rhinitis and asthma was significantly increased in our EE cohort compared with the general Australian population. A total of 24% of our cohort of patients with EE had a history of anaphylaxis. CONCLUSION: In children with EE, the sensitization to inhalant allergens increases with age, particularly after 4 years. Also, specific enquiry about severe food reactions in patients presenting with EE is strongly recommended as it appears this patient group has a high incidence of anaphylaxis.

Serine proteases, their inhibitors and allergy.

This paper reviews four serine protease inhibitors and three protease gene defects that are associated with allergic conditions, suggesting an important role for these genes and their products in the development of allergy. Serine protease inhibitors may have a therapeutic potential in the treatment of allergy.

Genetic factors contribute to bleeding after cardiac surgery.

BACKGROUND: Postoperative bleeding remains a common, serious problem for cardiac surgery patients, with striking inter-patient variability poorly explained by clinical, procedural, and biological markers. OBJECTIVE: We tested the hypothesis that genetic polymorphisms of coagulation proteins and platelet glycoproteins are associated with bleeding after cardiac surgery. PATIENTS/METHODS: Seven hundred and eighty patients undergoing aortocoronary surgery with cardiopulmonary bypass were studied. Clinical covariates previously associated with bleeding were recorded and DNA isolated from preoperative blood. Matrix Assisted Laser Desorption/Ionization, Time-Of-Flight (MALDI-TOF) mass spectroscopy or polymerase chain reaction were used for genotype analysis. Multivariable linear regression modeling, including all genetic main effects and two-way gene-gene interactions, related clinical and genetic predictors to bleeding from the thorax and mediastinum. RESULTS: Nineteen candidate polymorphisms were assessed; seven [GPIaIIa-52C>T and 807C>T, GPIb alpha 524C>T, tissue factor-603A>G, prothrombin 20210G>A, tissue factor pathway inhibitor-399C>T, and angiotensin converting enzyme (ACE) deletion/insertion] demonstrate significant association with bleeding (P < 0.01). Adding genetic to clinical predictors results improves the model, doubling overall ability to predict bleeding (P < 0.01). CONCLUSIONS: We identified seven genetic polymorphisms associated with bleeding after cardiac surgery. Genetic factors appear primarily independent of, and explain at least as much variation in bleeding as clinical covariates; combining genetic and clinical factors double our ability to predict bleeding after cardiac surgery. Accounting for genotype may be necessary when stratifying risk of bleeding after cardiac surgery.

Grandparents use of new communication technologies in a European perspective.

This study examined the pattern of use of different forms of contact between grandparents and grandchildren, and especially the use of new technologies (SMS, e-mail) and factors affecting this. Questionnaire data are reported from 408 grandparents in the UK, Spain, Finland and Estonia, regarding contacts with grandchildren mostly in the 10-15-year age range. Face-to-face contact remained the most frequent mean, followed closely by landline telephone; there was moderate use of mobile phones, and many used letters/cards occasionally; and a minority used SMS and e-mails (about one-half to one-third of those with mobile phones, and networked computers, respectively). When contacting grandchildren, most grandparents accumulate different forms of contact, but others compensate some forms of contact. There were no differences by age of grandparent, but grandmothers made more use of e-mail than grandfathers, as did more highly educated grandparents and those with older grandchildren. Implications for use of Information and Communication Technology by older people are discussed.

Site-specific PEGylation of hemoglobin at Cys-93(beta): correlation between the colligative properties of the PEGylated protein and the length of the conjugated PEG chain.

Increasing the molecular size of acellular hemoglobin (Hb) has been proposed as an approach to reduce its undesirable vasoactive properties. The finding that bovine Hb surface decorated with about 10 copies of PEG5K per tetramer is vasoactive provides support for this concept. The PEGylated bovine Hb has a strikingly larger molecular radius than HbA (1). The colligative properties of the PEGylated bovine Hb are distinct from those of HbA and even polymerized Hb, suggesting a role for the colligative properties of PEGylated Hb in neutralizing the vasoactivity of acellular Hb. To correlate the colligative properties of surface-decorated Hb with the mass of the PEG attached and also its vasoactivity, we have developed a new maleimide-based protocol for the site-specific conjugation of PEG to Hb, taking advantage of the unusually high reactivity of Cys-93(beta) of oxy HbA and the high reactivity of the maleimide to protein thiols. PEG chains of 5, 10, and 20 kDa have been functionalized at one of their hydroxyl groups with a maleidophenyl moiety through a carbamate linkage and used to conjugate the PEG chains at the beta-93 Cys of HbA to generate PEGylated Hbs carrying two copies of PEG (of varying chain length) per tetramer. Homogeneous preparations of (SP-PEG5K)(2)-HbA, (SP-PEG10K)(2)-HbA, and (SP-PEG20K)(2)-HbA have been isolated by ion exchange chromatography. The oxygen affinity of Hb is increased slightly on PEGylation, but the length of the PEG-chain had very little additional influence on the O(2) affinity. Both the hydrodynamic volume and the molecular radius of the Hb increased on surface decoration with PEG and exhibited a linear correlation with the mass of the PEG chain attached. On the other hand, both the viscosity and the colloidal osmotic pressure (COP) of the PEGylated Hbs exhibited an exponential increase with the increase in PEG chain length. In contrast to the molecular volume, viscosity, and COP, the vasoactivity of the PEGylated Hbs was not a direct correlate of the PEG chain length. There appeared to be a threshold for the PEG chain length beyond which the protection against vasoactivity is decreased. These results suggest that the modulation of the vasoactivity of Hb by PEG could be a function of the surface shielding afforded by the PEG, the latter being a function of the disposition of the PEG chain on the protein surface, which in turn is a function of the length of the PEG chain. Thus, the biochemically homogeneous PEGylated Hbs described in the present study, surface-decorated with PEG chains of appropriate size, could serve as potential candidates for Hb-based oxygen carriers.

Food allergy in children.

Food allergies are increasing in prevalence and as a disease burden throughout the world, however they seem to increasingly affect countries with a formerly low prevalence. Consideration and diagnosis of food allergies are important as it has ramifications that affect a child's diet, care at school and home and is recognised to be associated with anxiety of parents, family and care takers. Food allergies vary significantly between countries, however nut allergies appear to be widely associated with serious reactions and death. The value of specific food immunoglobulin E (IgE) and skin prick tests (SPT) has been extensively analysed in children in recent years and can provide very useful information in an appropriately selected population. Diagnosis may require formal challenges to confirm a genuine allergic reaction condition rather than an intolerance reaction due to other mechanisms. The medical care of a food allergic child requires concurrent dietary advice and management, risk avoidance and emergency management plans. Reintroduction of foods occurs when the risk profile is appropriate based mainly on the predictive information obtained by SPTs and specific IgE levels. Fortunately allergies to egg and milk resolve by 3-5 years in about 80% of children. There have been some recent advances in immunotherapeutic approaches to food allergy although this has not translated to success in human treatment to date.

Report of a substudy on warm versus cold cardiopulmonary bypass: changes in creatinine clearance.

BACKGROUND: Renal dysfunction remains a major complication of cardiac operations. There is concern regarding the possibility of increased renal injury during warm cardiopulmonary bypass (CPB). Therefore, we tested the hypothesis that warm CPB is associated with a greater reduction in creatinine clearance after cardiac surgery than hypothermic CPB. METHODS: We randomly assigned 300 patients who had elective coronary artery bypass grafting to warm (35.5 to 36.5 degrees C) or cold (28 degrees C to 30 degrees C) CPB. Preoperative and peak postoperative serum creatinine values were recorded. Creatinine clearance was estimated using the Cockroft Gault equation. Univariate and multivariable analyses were performed to test the association of CPB temperature and perioperative change in creatinine clearance. RESULTS: Demographic variables were similar between groups. Multivariable analysis did not confirm an association between temperature and change in creatinine clearance (p = 0.87). CONCLUSIONS: We did not confirm an association between warm CPB and increased renal dysfunction after cardiac operations compared with hypothermic CPB.

Prospective randomized trial of normothermic versus hypothermic cardiopulmonary bypass on cognitive function after coronary artery bypass graft surgery.

BACKGROUND: Despite significant advances in cardiopulmonary bypass (CPB) technology, surgical techniques, and anesthetic management, central nervous system complications occur in a large percentage of patients undergoing surgery requiring CPB. Many centers are switching to normothermic CPB because of shorter CPB and operating room times and improved myocardial protection. The authors hypothesized that, compared with normothermia, hypothermic CPB would result in superior neurologic and neurocognitive function after coronary artery bypass graft surgery. METHODS: Three hundred patients undergoing elective coronary artery bypass graft surgery were prospectively enrolled and randomly assigned to either normothermic (35.5-36.5 degrees C) or hypothermic (28-30 degrees C) CPB. A battery of neurocognitive tests was performed preoperatively and at 6 weeks after surgery. Four distinct cognitive domains were identified and standardized using factor analysis and were then compared on a continuous scale. RESULTS: Two hundred twenty-seven patients participated in 6-week follow-up testing. There were no differences in neurologic or neurocognitive outcomes between normothermic and hypothermic groups in multivariable models, adjusting for covariable effects of baseline cognitive function, age, and years of education, as well as interaction of these with temperature treatment. CONCLUSIONS: Hypothermic CPB does not provide additional central nervous system protection in adult cardiac surgical patients who were maintained at either 30 or 35 degrees C during CPB.

Leucocyte populations in respiratory syncytial virus-induced bronchiolitis.

OBJECTIVES: To enumerate the cellular composition of the airways in infants with acute bronchiolitis. METHODOLOGY: Cells were obtained by airway lavage from the upper and lower airway and the peripheral blood of infants with respiratory syncytial virus (RSV)+ bronchiolitis, RSV- bronchiolitis and age-matched controls. RESULTS: Neutrophils are the predominant cells present in the upper and lower airway. Neutrophils are present at a higher number/unit volume in the airway than in the peripheral blood. CONCLUSIONS: Neutrophils, being the dominant cellular infiltrate into the airway, are likely to contribute to the pathophysiology of bronchiolitis. Therapies targeted at limiting neutrophil influx or neutrophil-mediated damage in the airway may have a therapeutic role.

Depressive symptoms and outcome of coronary artery bypass grafting.

BACKGROUND: Depressive symptoms are an independent risk factor for outcome in patients with cardiac disease, but their effect on outcome among patients undergoing coronary artery bypass grafting is not well understood. OBJECTIVES: To determine whether or not clinical variables including length of stay, readmission rates, and mortality are related to patients' level of depressive symptoms before and after coronary artery bypass grafting. METHODS: An observational, longitudinal design was used. The Medical Outcomes Study 36-item short-form health survey was used to collect data on depressive symptoms in 416 patients undergoing coronary artery bypass grafting. The distribution of depressive symptoms was correlated with length of stay after the procedure, readmission, and mortality. RESULTS: The level of depressive symptoms before coronary artery bypass grafting correlated with the level of depressive symptoms at 6 weeks follow-up, both for the individual items "feeling down in the dumps" (r = 0.24, P = .009) and "feeling downhearted" (r = 0.36, P < .001) and for the overall score on the Mental Health scale (r = 0.40, P < .001). Feeling down in the dumps (P = .007) and overall scores on the Mental Health scale (P = .02) were significantly related to readmission within 6 months. CONCLUSIONS: Higher levels of depressive symptoms before coronary artery bypass grafting are related to higher hospital readmission rates 6 months after the procedure. Nurses can play a pivotal role in determining which patients require evaluation, educating patients, and initiating effective treatment, which may prevent readmission related to depressive symptoms.

Abciximab and bleeding during coronary surgery: results from the EPILOG and EPISTENT trials. Improve Long-term Outcome with abciximab GP IIb/IIIa blockade. Evaluation of Platelet IIb/IIIa Inhibition in STENTing.

BACKGROUND: Abciximab during percutaneous coronary revascularization reduces ischemic complications, but concern exists regarding increased bleeding risk should emergency coronary surgical procedures be required. METHODS: Outcomes were assessed among 85 patients who required coronary artery bypass grafting operations after coronary intervention in two randomized placebo-controlled trials of abciximab. Comparisons were made between patients in the pooled placebo and abciximab groups. RESULTS: The incidence of coronary surgical procedures was 2.17% and 1.28% among patients randomized to placebo and abciximab, respectively (p = 0.021). Platelet transfusions were administered to 32% and 52% of patients in the placebo and abciximab groups, respectively (p = 0.059). Rates of major blood loss were 79% and 88% in the placebo and abciximab groups, respectively (p = 0.27); transfusions of packed red blood cells or whole blood were administered in 74% and 80% of patients, respectively (p = 0.53). Surgical reexploration for bleeding was required in 3% and 12% of patients, respectively. Death and myocardial infarction tended to occur less frequently among patients who had received abciximab. CONCLUSIONS: Urgent coronary artery bypass grafting operations can be performed without an incremental increase in major hemorrhagic risk among patients on abciximab therapy.

Current status of cardiac surgery in the abciximab-treated patient.

BACKGROUND: Early surgical experience with abciximab and other glycoprotein (GP) IIb/IIIa receptor antagonists suggested a tendency toward excessive bleeding in patients treated with these agents. With increased use of GP IIb/IIIa inhibitors, cardiac surgeons have become aware of their hazards, as well as potential benefits, during and after cardiac surgery. Although published experience with the GP IIb/IIIa inhibitor abciximab is limited in scope, it suggests management guidelines for urgent coronary artery bypass grafting in abciximab-treated patients. As more urgent and elective surgical data are presented, a clearer picture of true bleeding risk will evolve. METHODS: Two large retrospective studies examining reexploration for postoperative bleeding have identified risk factors, including advanced age, preoperative renal dysfunction, and operation/reoperation other than coronary artery bypass grafting. Other risk factors for transfusion requirement and increased morbidity and mortality are emergent operation, postoperative coagulopathy, and prolonged bypass time. RESULTS: To minimize real and perceived bleeding effects, some authors have suggested delaying operation until platelet function has normalized, employing platelet transfusion in patients in whom delay is not possible, and exacting heparin management during cardiopulmonary bypass. Later reports have not noted increased bleeding when incorporating these modifications plus early platelet transfusion, if required. Further experience with abciximab removal and reversal may also ultimately reduce or eliminate excess transfusion requirements. CONCLUSIONS: Surgeons should work closely with perfusionists and anesthesiologists on issues of heparinization in the abciximab-treated patient. The apparent paradox of preserved platelet numbers and depressed platelet function with abciximab use has led to speculation about a role for this agent and other shorter-acting GP IIb/IIIa inhibitors for "platelet anesthesia" during cardiopulmonary bypass. With careful surgical care, GP IIb/IIIa receptor antagonists can maintain and improve beneficial outcomes.

Intraoperative physiologic variables and outcome in cardiac surgery: Part I. In-hospital mortality.

BACKGROUND: Risk stratification schemes have been developed to predict outcome of coronary artery bypass grafting (CABG) procedures, which are predominately based upon unalterable preoperative patient characteristics. The purpose of this study was to determine if minimum intraoperative hematocrit, maximum glucose concentration, mean arterial pressure on cardiopulmonary bypass, or duration of bypass influence risk-adjusted in-hospital mortality after CABG. METHODS: Outcome data from 2,862 CABG patients were merged with intraoperative physiologic data. A preoperative mortality risk index was calculated for each patient. Variables found significant (p<0.05) by univariate logistic regression were tested in a multiple variable model to determine risk-adjusted association with mortality. RESULTS: Overall mortality rate was 1.85%. The preoperative risk index was significantly associated with mortality (p = 0.0001). No significant association was present between mortality and intraoperative variables. Preexisting hypertension was an independent predictor of mortality after controlling for risk index and bypass duration. CONCLUSIONS: Preexisting hypertension proved to be an independent predictor of mortality in our patient population. This study found no evidence to support the hypothesis that mean arterial pressure less than 50 mm Hg, lower hematocrit, or elevated glucose while on bypass increases in-hospital mortality.

Intraoperative physiologic variables and outcome in cardiac surgery: Part II. Neurologic outcome.

BACKGROUND: The impact of alterable physiologic variables on neurologic outcome after coronary artery bypass grafting procedures is unknown. The purpose of this study was to determine whether minimum intraoperative hematocrit, maximum glucose concentration, or mean arterial pressure during cardiopulmonary bypass influences risk-adjusted neurologic outcome after coronary artery bypass grafting. METHODS: Outcome data from 2,862 patients undergoing coronary artery bypass grafting were merged with intraoperative physiologic data. A preoperative stroke risk index was calculated for each patient. Variables found significant by univariate logistic regression were tested in a multivariable model to determine association with outcome. RESULTS: The incidence of stroke or coma in the study population was 1.3%. After controlling for stroke risk and bypass time, only an index of low mean arterial pressure during bypass retained a significant inverse association with outcome (p = 0.0304). CONCLUSIONS: This study found no evidence that glucose concentration or minimum hematocrit are associated with major adverse neurologic outcome. The association between lower pressure during bypass and decreased incidence of stroke or coma persisted in all risk groups. This points to mechanisms other than hypoperfusion as the primary cause of neurologic injury associated with cardiac surgery.