Faculty Bibliography

Numerous changes in GABAergic neurons, receptors, and inhibitory mechanisms have been described in temporal lobe epilepsy (TLE), either in humans or in animal models. Nevertheless, there remains a common assumption that epilepsy can be explained by simply an insufficiency of GABAergic inhibition. Alternatively, investigators have suggested that there is hyperinhibition that masks an underlying hyperexcitability. Here we examine the status epilepticus (SE) models of TLE and focus on the dentate gyrus of the hippocampus, where a great deal of data have been collected. The types of GABAergic neurons and GABAA receptors are summarized under normal conditions and after SE. The role of GABA in development and in adult neurogenesis is discussed. We suggest that instead of "too little or too much" GABA there is a complexity of changes after SE that makes the emergence of chronic seizures (epileptogenesis) difficult to understand mechanistically, and difficult to treat. We also suggest that this complexity arises, at least in part, because of the remarkable plasticity of GABAergic neurons and GABAA receptors in response to insult or injury.

High-frequency ripple oscillations, observed most prominently in the hippocampal CA1 pyramidal layer, are associated with memory consolidation. The cellular and network mechanisms underlying the generation, frequency control, and spatial coherence of the rhythm are poorly understood. Using multisite optogenetic manipulations in freely behaving rodents, we found that depolarization of a small group of nearby pyramidal cells was sufficient to induce high-frequency oscillations, whereas closed-loop silencing of pyramidal cells or activation of parvalbumin- (PV) or somatostatin-immunoreactive interneurons aborted spontaneously occurring ripples. Focal pharmacological blockade of GABAA receptors abolished ripples. Localized PV interneuron activation paced ensemble spiking, and simultaneous induction of high-frequency oscillations at multiple locations resulted in a temporally coherent pattern mediated by phase-locked interneuron spiking. These results constrain competing models of ripple generation and indicate that temporally precise local interactions between excitatory and inhibitory neurons support ripple generation in the intact hippocampus.

The International League Against Epilepsy (ILAE) defined a seizure as "a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain." This definition has been used since the era of Hughlings Jackson, and does not take into account subsequent advances made in epilepsy and neuroscience research. The clinical diagnosis of a seizure is empirical, based upon constellations of certain signs and symptoms, while simultaneously ruling out a list of potential imitators of seizures. Seizures should be delimited in time, but the borders of ictal (during a seizure), interictal (between seizures) and postictal (after a seizure) often are indistinct. EEG recording is potentially very helpful for confirmation, classification and localization. About a half-dozen common EEG patterns are encountered during seizures. Clinicians rely on researchers to answer such questions as why seizures start, spread and stop, whether seizures involve increased synchrony, the extent to which extra-cortical structures are involved, and how to identify the seizure network and at what points interventions are likely to be helpful. Basic scientists have different challenges in use of the word 'seizure,' such as distinguishing seizures from normal behavior, which would seem easy but can be very difficult because some rodents have EEG activity during normal behavior that resembles spike-wave discharge or bursts of rhythmic spiking. It is also important to define when a seizure begins and stops so that seizures can be quantified accurately for pre-clinical studies. When asking what causes seizures, the transition to a seizure and differentiating the pre-ictal, ictal and post-ictal state is also important because what occurs before a seizure could be causal and may warrant further investigation for that reason. These and other issues are discussed by three epilepsy researchers with clinical and basic science expertise.

When all of the epilepsies are considered, sex differences are not always clear, despite the fact that many sex differences are known in the normal brain. Sex differences in epilepsy in laboratory animals are also unclear, although robust effects of sex on seizures have been reported, and numerous effects of gonadal steroids have been shown throughout the rodent brain. Here we discuss several reasons why sex differences in seizure susceptibility are unclear or are difficult to study. Examples of robust sex differences in laboratory rats, such as the relative resistance of adult female rats to the chemoconvulsant pilocarpine compared to males, are described. We also describe a novel method that has shed light on sex differences in neuropathology, which is a relatively new techniques that will potentially contribute to sex differences research in the future. The assay we highlight uses the neuronal nuclear antigen NeuN to probe sex differences in adult male and female rats and mice. In females, weak NeuN expression defines a sex difference that previous neuropathological studies have not described. We also show that in adult rats, social isolation stress can obscure the normal effects of 17beta-estradiol to increase excitability in area CA3 of hippocampus. These data underscore the importance of controlling behavioral stress in studies of seizure susceptibility in rodents and suggest that behavioral stress may be one factor that has led to inconsistencies in outcomes of sex differences research. These and other issues have made it difficult to translate our increasing knowledge about the effects of gonadal hormones on the brain to improved treatment for men and women with epilepsy.

CHF1/Hey2 is a Notch-responsive basic helix-loop-helix transcription factor involved in cardiac development. Common variants in Hey2 are associated with Brugada syndrome. We hypothesized that absence of CHF1/Hey2 would result in abnormal cellular electrical activity, altered cardiac conduction system (CCS) development, and increased arrhythmogenesis. We isolated neonatal CHF/Hey2-knockout (KO) cardiac myocytes and measured action potentials and ion channel subunit gene expression. We also crossed myocardial-specific CHF1/Hey2-KO mice with cardiac conduction system LacZ reporter mice and stained for conduction system tissue. We also performed ambulatory ECG monitoring for arrhythmias and heart rate variability. Neonatal cardiomyocytes from CHF1/Hey2-KO mice demonstrate a 50% reduction in action potential dV/dT, a 50-75% reduction in SCN5A, KCNJ2, and CACNA1C ion channel subunit gene expression, and an increase in delayed afterdepolarizations from 0/min to 12/min. CHF1/Hey2 cKO CCS-lacZ mice have a approximately 3-fold increase in amount of CCS tissue. Ambulatory ECG monitoring showed no difference in cardiac conduction, arrhythmias, or heart rate variability. Wild-type cells or animals were used in all experiments. CHF1/Hey2 may contribute to Brugada syndrome by influencing the expression of SCN5A and formation of the cardiac conduction system, but its absence does not cause baseline conduction defects or arrhythmias in the adult mouse.-Hartman, M. E., Liu, Y., Zhu, W.-Z., Chien, W.-M., Weldy, C. S., Fishman, G. I., Laflamme, M. A., Chin, M. T. Myocardial deletion of transcription factor CHF1/Hey2 results in altered myocyte action potential and mild conduction system expansion but does not alter conduction system function or promote spontaneous arrhythmias.

INTRODUCTION: and Objectives: To examine kidney stone disease as a potential risk factor for chronic kidney disease (CKD), end-stage kidney disease and treatment with dialysis (ESKD). METHODS: The National Health and Nutrition Examination Survey (NHANES 2007-2010) database was interrogated for patients with a history of kidney stones. Demographics and comorbid conditions including age, sex, body mass index (BMI), diabetes, hemoglobin A1c, hypertension, gout and smoking were also assessed. Multivariate analysis adjusting for patient demographics and comorbidities was performed to assess differences in the prevalence of CKD and treatment with dialysis between the two groups. History of nephrolithiasis was assessed by the question "Have you ever had kidney stones?" CKD was defined as patients with either an eGFR of < 60 mL/min/1.73 m2 or a urinary albumin to creatinine ratio >30 mg/g or both. Statistical calculations were performed using Stata software (StataCorp LP, Texas) with determinations of p-values and 95% confidence intervals where appropriate. RESULTS: The study included an analysis of 5,971 NHANES participants for whom data on CKD and kidney stones was available, of whom 521 reported a history of kidney stones. On multivariate analysis, a history of kidney stones was associated with CKD and treatment with dialysis (OR 1.50 (1.10-2.04) p= 0.013, and 2.37 (1.13- 4.96) p=0.025). This difference appeared to be driven by women, where a history of kidney stones was associated with a higher prevalence of CKD (OR 1.76 (1.13-2.763) p=0.016) and treatment with dialysis (OR 3.26 (1.48-7.16) p=0.004). There was not a significant association between kidney stone history and CKD or treatment with dialysis in men. CONCLUSIONS: Kidney stone history is associated with an increased risk of CKD and treatment with dialysis among women even after adjusting for co-morbid conditions. Large-scale prospective studies are needed to further characterize the relationship between nephrolithiasis and CKD.

PURPOSE: The purpose of this guideline is to provide a clinical framework for the diagnosis, prevention and follow-up of adult patients with kidney stones based on the best available published literature. MATERIALS AND METHODS: The primary source of evidence for this guideline was the systematic review conducted by the Agency for Healthcare Research and Quality on recurrent nephrolithiasis in adults. To augment and broaden the body of evidence in the AHRQ report, the AUA conducted supplementary searches for articles published from 2007 through 2012 that were systematically reviewed using a methodology developed a priori. In total, these sources yielded 46 studies that were used to form evidence-based guideline statements. In the absence of sufficient evidence, additional statements were developed as Clinical Principles and Expert Opinions. RESULTS: Guideline statements were created to inform clinicians regarding the use of a screening evaluation for first-time and recurrent stone formers, the appropriate initiation of a metabolic evaluation in select patients and recommendations for the initiation and follow-up of medication and/or dietary measures in specific patients. CONCLUSIONS: A variety of medications and dietary measures have been evaluated with greater or less rigor for their efficacy in reducing recurrence rates in stone formers. The guideline statements offered in this document provide a simple, evidence-based approach to identify high-risk or interested stone-forming patients for whom medical and dietary therapy based on metabolic testing and close follow-up is likely to be effective in reducing stone recurrence.

Mortality is highest in the first months of maintenance hemodialysis (HD) therapy. In many Western countries, patients who transition to kidney replacement therapy usually begin thrice-weekly HD regardless of their level of residual kidney function (RKF). RKF is a major predictor of survival. RKF may decline more rapidly with thrice-weekly HD treatments, is associated with a reduced need for dialytic solute clearance, and is an important factor in the prescription of peritoneal dialysis. In this article, we review the concept of incremental HD, in which weekly dialysis dose, in particular HD treatment frequency, is based on a variety of clinical factors, such as RKF (including urine output > 0.5L/d), volume status, cardiovascular symptoms, body size, potassium and phosphorus levels, nutritional status, hemoglobin level, comorbid conditions, hospitalizations, and health-related quality of life. These 10 clinical criteria may identify which patients might benefit from beginning maintenance HD therapy twice weekly. Periodic monitoring of these criteria will determine the timing for increasing dialysis dose and frequency. We recognize that twice-weekly HD represents a major paradigm shift for many clinicians and jurisdictions. Therefore, we propose conducting randomized controlled trials of twice-weekly versus thrice-weekly HD to assess the potential of twice-weekly HD to improve survival and health-related quality of life while simultaneously reducing costs, protecting fragile vascular accesses, and optimizing resource use during the first year of hemodialysis therapy. Such incremental and individualized HD therapy may prove to be the most appropriate approach for transitioning to dialytic therapy.

A literature review performed by the EXtracorporeal TReatments In Poisoning (EXTRIP) workgroup highlighted deficiencies in the existing literature, especially the reporting of case studies. Although general reporting guidelines exist for case studies, there are none in the specific field of extracorporeal treatments in toxicology. Our goal was to construct and propose a checklist that systematically outlines the minimum essential items to be reported in a case study of poisoned patients undergoing extracorporeal treatments. Through a modified two-round Delphi technique, panelists (mostly chosen from the EXTRIP workgroup) were asked to vote on the pertinence of a set of items to identify those considered minimally essential for reporting complete and accurate case reports. Furthermore, independent raters validated the clarity of each selected items between each round of voting. All case reports containing data on extracorporeal treatments in poisoning published in Medline in 2011 were reviewed during the external validation rounds. Twenty-one panelists (20 from the EXTRIP workgroup and an invited expert on pharmacology reporting guidelines) participated in the modified Delphi technique. This group included journal editors and experts in nephrology, clinical toxicology, critical care medicine, emergency medicine, and clinical pharmacology. Three independent raters participated in the validation rounds. Panelists voted on a total of 144 items in the first round and 137 items in the second round, with response rates of 96.3% and 98.3%, respectively. Twenty case reports were evaluated at each validation round and the independent raters' response rate was 99.6% and 98.8% per validation round. The final checklist consists of 114 items considered essential for case study reporting. This methodology of alternate voting and external validation rounds was useful in developing the first reporting guideline for case studies in the field of extracorporeal treatments in poisoning. We believe that this guideline will improve the completeness and transparency of published case reports and that the systematic aggregation of information from case reports may provide early signals of effectiveness and/or harm, thereby improving healthcare decision-making.