Immunopathogenesis and biomarkers of recurrent atrial fibrillation following ablation therapy in patients with preexisting atrial fibrillation.

INTRODUCTION: Recurrent atrial fibrillation (RAF) following ablation therapy occurs in about 50% of patients. The pathogenesis of RAF is unknown, but is believed to be driven by atrial remodeling in the setting of background inflammation. Structural, electrophysiological and mechanical remodeling has been associated with atrial fibrillation (AF). Inflammation and fibrotic remodeling are the major factors perpetuating AF, as mediators released from the atrial tissues and cardiomyocytes due to mechanical and surgical injury could initiate the inflammatory process. In this article, we have critically reviewed the key mediators that may serve as potential biomarkers to predict RAF. Areas covered: Damage associated molecular patterns, heat shock proteins, inflammatory cytokines, non-inflammatory markers, markers of inflammatory cell activity, and markers of collagen deposition and metabolism are evaluated as potential biomarkers with molecular treatment options in RAF. Expert commentary: Establishing biomarkers to predict RAF could be useful in reducing morbidity and mortality. Investigations into the role of DAMPs participating in a sterile immune response may provide greater insight into the pathogenesis of RAF. Markers evaluating immune cell activity, collagen deposition, and levels of heat shock proteins show the greatest promise as potential biomarkers to predict RAF and develop novel therapies.

Mechanisms, diagnosis, and treatment of heart failure with preserved ejection fraction and diastolic dysfunction.

INTRODUCTION: Heart failure with preserved ejection fraction (HFpEF) continues to be a major challenge for clinicians. Many crucial aspects of the syndrome remain unclear, including the exact pathophysiology, early diagnosis, and treatment. Patients with HFpEF are often asymptomatic late into the disease process, and treatment with medications commonly used in heart failure with reduced ejection fraction (HFrEF) has not been proven to be beneficial. In addition, the confusion of similar terms with HFpEF, such as diastolic heart failure, and diastolic dysfunction (DD), has led to a misunderstanding of the true scope of HFpEF. Areas covered: In this review, authors highlight the differences in terminology and critically review the current knowledge on the underlying mechanisms, diagnosis, and latest treatment strategies of HFpEF. Expert commentary: While significant advances have been made in the understanding of HFpEF, the definitive diagnosis of HFpEF continues to be difficult. The development of improved and standardized methods for detecting DD has shown promise in identifying early HFpEF. However, even with early detection, there are few treatment options shown to provide mortality benefit warranting further investigation.

MetaPath: an electronic knowledge base for collating, exchanging and analyzing case studies of xenobiotic metabolism.

The MetaPath knowledge base was developed for the purpose of archiving, sharing and analyzing experimental data on metabolism, metabolic pathways and crucial supporting metadata. The MetaPath system grew out of the need to compile and organize the results of metabolism studies into a systematic database to facilitate data comparisons and evaluations. Specialized MetaPath data evaluation tools facilitate the review of pesticide metabolism data submitted for regulatory risk assessments as well as exchange of results of complex analyses used in regulation and research. Customized screen editors called Composers were developed to automate data entry into MetaPath while also streamlining the production of agency specific study summaries such as the Data Evaluation Records (DER) used by the US EPA Office of Pesticide Programs. Efforts are underway through an Organization for Economic Co-operation and Development (OECD) work group to extend the use of DER Composers as harmonized templates for rat metabolism, livestock residue, plant residue and environmental degradation studies.

Friendships and social interactions of school-aged children with migraine.

We set out to evaluate the friendships and social behaviour of school-aged children with migraine. Concern exists regarding the impact of paediatric migraine on daily activities and quality of life. We hypothesized that children with migraine would have fewer friends and be identified as more socially sensitive and isolated than comparison peers. Sixty-nine children with migraine participated in a school-based study of social functioning. A comparison sample without migraine included classmates matched for gender, race and age. Children with migraine had fewer friends at school; however, this effect was limited to those in elementary school. Behavioural difficulties were not found. Middle-school students with migraine were identified by peers as displaying higher levels of leadership and popularity than comparison peers. Concern may be warranted about the social functioning of pre-adolescent children with migraine; however, older children with migraine may function as well as or better than their peers.

Childhood obesity predicts adult metabolic syndrome: the Fels Longitudinal Study.

OBJECTIVES: To determine the age of significant divergence in body mass index (BMI) and waist circumference in adults with and without the metabolic syndrome, and to provide age- and sex-specific childhood values that predict adult metabolic syndrome. STUDY DESIGN: Part 1 of this study is a retrospective cohort study of 92 men and 59 women (mean age, 51 years) who had metabolic syndrome and 154 randomly selected adults matched for age and sex who did not have the syndrome. Part 2 is a study of predictive accuracy in a validation sample of 743 participants. RESULTS: The first appearance of differences between adults with and without metabolic syndrome occurred at ages 8 and 13 for BMI and 6 and 13 for waist circumference in boys and girls, respectively. Odds ratios (ORs) for the metabolic syndrome at 30 years and older ranged from 1.4 to 1.9 across age groups in boys and from 0.8 to 2.8 across age groups in girls if BMI exceeded criterion values in childhood. The corresponding ORs for waist circumference ranged from 2.5 to 31.4 in boys and 1.7 to 2.5 in girls. These ORs increased with the number of examinations. CONCLUSIONS: Children with BMI and waist circumference values exceeding the established criterion values are at increased risk for the adult metabolic syndrome.

New therapies and preventive approaches for necrotizing enterocolitis: report of a research planning workshop.

The National Institute of Child Health and Human Development and the Digestive Diseases Interagency Coordinating Committee held a workshop, chaired by Dr. W. Allan Walker, on July 10-11, 2006, to identify promising leads in necrotizing enterocolitis (NEC) research. The goals of the workshop were to identify new approaches to the prevention and treatment of NEC, to define basic and translational mechanisms of potential approaches to NEC, and to develop recommendations for clinical studies to reduce the incidence of NEC. Workshop participants implicated prematurity, introduction of enteral feedings, gastrointestinal bacterial colonization, gut motility, proinflammatory cytokines, impaired gut blood flow, and various neonatal complications in the pathogenesis of NEC. They concluded that a unifying hypothesis encompassing these pathogenetic factors is the uncontrolled exuberant inflammatory response to bacterial colonization that characterizes the intestine of premature infants. The inflammatory cascade appears to offer multiple targets for interventions with a variety of anti-inflammatory agents, including human milk and probiotics. Because of the rapidity with which the inflammatory response gets out of control in infants with NEC, workshop participants agreed that searching for ways to prevent NEC will be more rewarding than trying to identify ways to treat the condition once it has become established.

Systolic blood pressure in childhood predicts hypertension and metabolic syndrome later in life.

OBJECTIVE: The goal was to link hypertension and the metabolic syndrome in adulthood directly to blood pressures measured decades earlier for the same individuals as children and to establish criterion values for blood pressure that predict hypertension and the metabolic syndrome later in life. METHODS: We analyzed serial data for 240 men and 253 women in the Fels Longitudinal Study. We derived age- and gender-specific childhood blood pressures that predict hypertension and the metabolic syndrome in adulthood, and we validated these criterion values in a larger sample. RESULTS: Blood pressure diverged between adults with and without the metabolic syndrome beginning at age 5 for boys and age 8 for girls. The odds ratios for developing hypertension at > or = 30 years of age ranged from 1.1 for 14- to 18-year-old boys to 3.8 for 5- to 7-year-old boys and from 2.7 for 8- to 13-year-old girls to 4.5 for 5- to 7-year-old girls, if their blood pressure exceeded criterion values at a single examination in childhood. The corresponding odds ratios for the metabolic syndrome, with or without hypertension, ranged from 1.2 for 14- to 18-year-old boys to 2.6 for 8- to 13-year-old boys and from 1.5 for 14- to 18-year-old girls to 3.1 for 5- to 7-year-old girls. The relative risk of adult hypertension ranged from 1.5 to 3.8 for boys and from 1.5 to 4.7 for girls, and that of the metabolic syndrome ranged from 1.1 to 1.8 for boys and from 1.2 to 5.6 for girls. These relative risks varied directly with the number of examinations at which systolic blood pressure exceeded criterion values. CONCLUSION: Children with systolic blood pressures above the criterion values established in this longitudinal study are at increased risk of hypertension and the metabolic syndrome later in life.

Use of trout liver slices to enhance mechanistic interpretation of estrogen receptor binding for cost-effective prioritization of chemicals within large inventories.

The cost of testing chemicals as reproductive toxicants precludes the possibility of evaluating large chemical inventories without a robust strategyfor prioritizing chemicals to test. The use of quantitative structure-activity relationships in early hazard identification is a cost-effective prioritization tool, but in the absence of systematic collection of interpretable test data upon which models are formulated, these techniques fall short of their intended use. An approach is presented for narrowing the focus of candidate ED chemicals using two in vitro assays: one optimized to measure the potential of chemicals to bind rainbow trout estrogen receptors (rtER), and a second to enhance interpretation of receptor binding data in a relevant biological system (i.e., fish liver tissue). Results of rtER competitive binding assays for 16 chemicals yielded calculable relative binding affinities (RBA) from 179 to 0.0006% for 13 chemicals and partial or no binding for an additional 3 chemicals. Eleven lower to no affinity chemicals (RBA < 0.1%) were further tested in trout liver slices to measure induction of rtER-dependent vitellogenin (VTG) mRNA in the presence of chemical passive partitioning (from media to multiple hepatocyte layers in the slice) and liver xenobiotic metabolism. VTG induction in slices was observed in a concentration-dependent manner for eight chemicals tested that had produced complete displacement curves in binding assays, including the lowest affinity binder with an RBA of 0.0006%. Two chemicals with only partial binding curves up to their solubility limit did not induce VTG. The monohydroxy metabolite of methoxychlor was the only chemical tested that apparently bound rtER but did not induce VTG mRNA. Data are presented illustrating the utility of the two assays in combination for interpreting the role of metabolism in VTG induction, as well as the sensitivity of the assays for measuring enantiomer selective binding and ER-mediated induction. The combined approach appears particularly useful in interpreting the potential relevance of extremely low affinity chemical binding to fish receptors (RBA = 0.01-0.0001%) within a defined toxicity pathway as a basis for prioritizing within large chemical inventories of environmental concern.

A systematic approach to simulating metabolism in computational toxicology. I. The TIMES heuristic modelling framework.

Designing biologically active chemicals and managing their risks requires a holistic perspective on the chemical-biological interactions that form the basis of selective toxicity. The balance of therapeutic and adverse outcomes for new drugs and pesticides is managed by shaping the probabilities for transport, metabolism, and molecular initiating events. For chemicals activated as well as detoxified by metabolism, selective toxicity may be considered in terms of relative probabilities, which shift dramatically across species as well as within a population, depending on many factors. The complexity in toxicology that results from metabolism has been troublesome in QSAR research because the parent structure is less relevant to predicting ultimate effects and finding reference species/conditions for metabolic rates seems hopeless. Even the complexity of comparative xenobiotic metabolism itself seems paradoxical in light of the evidence of highly conserved catabolic processes across species. Clearly, predicting the role of metabolism in selective toxicity and adverse health outcomes requires a probabilistic framework for deterministic models as well as the many factors shaping the metabolic probability distributions under specific conditions. This paper presents a tissue metabolism simulator (TIMES), which uses a heuristic algorithm to generate plausible metabolic maps from a comprehensive library of biotransformations and abiotic reactions and estimates for system-specific transformation probabilities. The transformation probabilities can be calibrated to specific reference conditions using transformation rate information from systematic testing. In the absence of rate data, a combinatorial algorithm is used to translate known metabolic maps taken from reference systems into best-fit transformation probabilities. Finally, toxicity test data itself can be used to shape the transformation probabilities for toxicity pathways in which the metabolic activation is the rate-limiting process leading to a toxic effect. The conceptual approach for metabolic simulation will be presented along with practical uses in forecasting plausible activated metabolites.

Pathways of lymphatic drainage from the breast.

BACKGROUND: The current standard for obtaining accurate sentinel lymph node (SLN) mapping is intraparenchymal lymphophilic dye/radiocolloid injection close to the breast tumor. We hypothesized that common lymphatic trunks drain both a large volume of breast parenchyma and skin and that intradermal or intraparenchymal routes flow to the same axillary node. METHODS: 99mTc-labeled filtered sulfur colloid was injected intradermally directly over the breast tumor in 119 patients. Blue dye was injected intraparenchymally in the same quadrant as the primary tumor (concordant quadrant) in 66 and in a discordant quadrant in 53 patients. During axillary exploration, both blue and gamma-emitting (hot) nodes were found. End points were SLNs that were hot and blue, either the same node or different nodes. RESULTS: In 62 (93.9%) of 66 of concordant quadrant and in 49 (92.5%) of 53 of discordant quadrant patients, the same SLN was both hot and blue (P = .99; Fisher's exact test). In eight cases in which two distinct nodes were blue and not hot and hot but not blue, the lymph nodes were very close to each other. CONCLUSIONS: The dermal and parenchymal lymphatics of the breast seemed to drain to the same axillary lymph nodes. Lymph from the entire breast seemed to drain through a small number of lymphatic trunks to one or two lymph nodes.

Postburn vitamin C infusions do not alter early postburn edema formation.

To determine whether vitamin C would alter burn induced edema accumulation, hind paw venous pressure, lymph flow (QL), and lymph-to-plasma protein ratio (CL/CP) were monitored in groups of 5 dogs before and 4 hours after 1) a 5 sec 100 degrees C or 90 degrees C foot paw scald; 2) intravenous vitamin C given 30 min before or after a 100 degrees C scald; and 3) vitamin C given 30 min after a 90 degrees C scald. Throughout the experiments, hind paw venous pressure was elevated and maintained by outflow restriction until steady state QL and (CL/CP)min were reached. Changes in protein permeability (CL/CP), fluid conductance properties (Kf) of the capillary membrane, and paw weight gain were determined. Compared with preburn values, scald uniformly produced significant (P < .05, ANOVA) increases in QL, CL/CP and Kf. Although preburn infusion of vitamin C significantly (P < .01) attenuated burn-induced increases in paw weight gain (36 +/- 3% vs 19 +/- 4%), neither of the groups that received vitamin C postburn experienced significant modulations in paw weight gain (28 +/- 4% vs 36 +/- 3% in 100 degrees C burn only; 23 +/- 4% vs 28 +/- 3% in 90 degrees C burn only) or in any of the variables used to monitor capillary membrane integrity. Vitamin C infusions initiated after graded scald produced no changes in the burn-induced increases in microvascular permeability or in edema formation measured at the injury site.

Lymph isolated from a regional scald injury produces a negative inotropic effect in dogs.

Large surface-area burns in patients have been associated with a severe impairment in cardiac performance, as evidenced by a decline in cardiac output. The mechanisms responsible for this profound myocardial dysfunction are largely unknown. We investigated the effects of lymph isolated from the scalded hind limb of dogs on regional myocardial blood flow, coronary vascular reactivity, and contractile performance. Dogs were instrumented with ultrasonic dimension crystals in the myocardium supplied by the left anterior descending (LAD) and by the left circumflex (LCx) coronary arteries. After cannulating a hind limb lymphatic, lymph was infused directly into the LAD before and after a 10-second 100 degrees C hind limb scald. Scalding alone did not alter myocardial contractile performance in the LAD or LCx regions, coronary artery blood flow, or systemic hemodynamics. Interestingly, postburn lymph infused into the LAD resulted in a 38% decline in LAD zone segment shortening (p < 0.01 vs baseline) that lasted throughout the 5-hour observation period. In contrast, segment shortening in the (control) LCx region was unaffected by postburn lymph injections into the LAD. Regional myocardial blood flow (radiolabeled microspheres) in the LAD and LCx regions was unchanged after scald injury or intracoronary injection of postburn lymph. In addition, LAD coronary artery vascular reactivity to acetylcholine and nitroglycerin was also unaffected by the regional thermal injury or by injection of lymph into the LAD. These data suggest that a regional scald injury results in the production and release of a potent myocardial depressant factor(s) that produces a direct negative inotropic effect on the canine myocardium.

Alpha-trinositol reduces edema formation at the site of scald injury.

BACKGROUND: The effects of alpha-trinositol (1D-myo-inositol-1,2,6-triphosphate, IP3) on burn-induced edema formation were investigated. METHODS: Lymph flow (QL; microliter/min) and lymph-to-plasma protein ratio (CL/CP) were monitored in groups of five to six dogs before and 4 hours after (1) a 5-second 100 degrees C or 90 degrees C foot paw scald; (2) IP3 (45 mg/kg intravenous bolus, then a 20 mg/kg/hr infusion) 30 minutes before or after 100 degrees C scald, or 30 minutes after 90 degrees C scald. Hind paw venous pressure was elevated and maintained by outflow restriction until reaching steady state QL and (CL/CP)min. Macromolecular reflection coefficient (1-CL/CP) was measured. Fluid filtration coefficient (Kf; ml/min/mm Hg/100 gm) was calculated. Relative paw weight gain (%) was measured. RESULTS: Compared with preburn values, scald uniformly produced significant increases in QL, CL/CP, and Kf, IP3 significantly (p < 0.02, ANOVA) reduced paw weight gain when given before, but not after, 100 degrees C burn (41% +/- 5% versus 18% +/- 7% preburn IP3 and 31% +/- 3% postburn IP3). Compared with 90 degrees C burn animals, postburn treatment significantly (p < 0.017) attenuated 4-hour increases in QL (550 +/- 87 versus 252 +/- 29 microliters/min), Kf (0.016 +/- 00 versus 0.007 +/- 00 microliter/min/mm/Hg/100 gm), and relative paw weight gain (28% +/- 3% versus 12% +/- 5%). CONCLUSIONS: alpha-Trinositol given after a 90 degrees C scald blunted edema formation at the site of scald, likely through reduced transmembrane fluid flux.

Severe ketoacidosis complicated by 'ecstasy' ingestion and prolonged exercise.

Ecstasy (3,4-methylenedioxymethamphetamine or MDMA) is used with increasing frequency as a recreational drug. Accumulated evidence over recent years indicates a growing demand for the drug with a corresponding increase in number of reports of adverse effects from its use. There are reported metabolic disturbances due to MDMA use. These, in addition to the prolonged exercise involved in dancing at 'raves' where MDMA may be used, may exacerbate ketoacidosis. We report two cases of ketoacidosis complicated by MDMA ingestion.

Caesarean section in undiagnosed Eisenmenger's syndrome. Report of a patient with a fatal outcome.

An obstetric patient is described in whom the first sign of cardiac disease was unexplained hypoxaemia during emergency anaesthesia for antepartum haemorrhage, with an eventual fatal outcome. The case highlights the importance of patient information at the booking clinic, and the implications of a raised haemaglobin in early pregnancy.