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Current understanding of the physiological underpinnings of normative pain processing is incomplete. Enhanced knowledge of these systems is necessary to advance our understanding of pain processes as well as to develop effective therapeutic interventions. Previous neuroimaging research suggests a network of interrelated brain regions that seem to be implicated in the processing and experience of pain. Among these, the dorsal anterior cingulate cortex (dACC) plays an important role in the affective aspects of pain signals. The current study leveraged functional MRS to investigate the underlying dynamic shifts in the neurometabolic signature of the human dACC at rest and during acute pain. Results provide support for increased glutamate levels following acute pain administration. Specifically, a 4.6% increase in glutamate was observed during moderate pressure pain compared with baseline. Exploratory analysis also revealed meaningful changes in dACC gamma aminobutyric acid in response to pain stimulation. These data contribute toward the characterization of neurometabolic shifts, which lend insight into the role of the dACC in the pain network. Further research in this area with larger sample sizes could contribute to the development of novel therapeutics or other advances in pain‐related outcomes. [ABSTRACT FROM AUTHOR]

Knee meniscus tears are one of the most common musculoskeletal injuries. While meniscus replacements using allografts or biomaterial‐based scaffolds are available, these treatments rarely result in integrated, functional tissue. Understanding mechanotransducive signaling cues that promote a meniscal cell regenerative phenotype is critical to developing therapies that promote tissue regeneration rather than fibrosis after injury. The purpose of this study was to develop a hyaluronic acid (HA) hydrogel system with tunable crosslinked network properties by modulating the degree of substitution (DoS) of reactive‐ene groups to investigate mechanotransducive cues received by meniscal fibrochondrocytes (MFCs) from their microenvironment. A thiol‐ene step‐growth polymerization crosslinking mechanism was employed using pentenoate‐functionalized hyaluronic acid (PHA) and dithiothreitol to achieve tunability of the chemical crosslinks and resulting network properties. Increased crosslink density, reduced swelling, and increased compressive modulus (60–1020 kPa) were observed with increasing DoS. Osmotic deswelling effects were apparent in PBS and DMEM+ compared to water; swelling ratios and compressive moduli were decreased in the ionic buffers. Frequency sweep studies showed storage and loss moduli of hydrogels at 1 Hz approach reported meniscus values and showed increasing viscous response with increasing DoS. The degradation rate increased with decreasing DoS. Lastly, modulating PHA hydrogel surface modulus resulted in control of MFC morphology, suggesting relatively soft hydrogels (E = 60 ± 35 kPa) promote more inner meniscus phenotype compared to rigid hydrogels (E = 610 ± 66 kPa). Overall, these results highlight the use of ‐ene DoS modulation in PHA hydrogels to tune crosslink density and physical properties to understand mechanotransduction mechanisms required to promote meniscus regeneration. [ABSTRACT FROM AUTHOR]

Substance use during the perinatal period and while parenting can pose a significant risk to children's safety and well‐being. Mothers who have experienced child maltreatment are more likely to use substances than mothers without a history of maltreatment. This study explores how child welfare social workers experience supporting young, maltreated mothers struggling with substance use to prevent the intergenerational transmission of child maltreatment. Semi‐structured in‐depth interviews were conducted with four social workers working with young mothers with a history of maltreatment and substance use. Interpretative Phenomenological Analysis revealed two themes: (1) grappling with system challenges and (2) supporting strategies for disrupting intergenerational transmission of child maltreatment. The results highlight the need for systemic changes around support for social workers who work with young mothers who use substances and have a history of maltreatment, and substance use treatment and mental health programs themselves. Mothers need access to prenatal programs that are trauma‐informed, non‐judgemental and that support participants' basic needs and parenting skills. [ABSTRACT FROM AUTHOR]

Mesenchymal stem/stromal cells (MSCs) are a heterogenous population of multipotent and highly secretory cells currently being investigated in the field of wound healing for their ability to augment tissue responses. The adaptive response of MSC populations to the rigid substrate of current 2D culture systems has been considered to result in a deterioration of regenerative 'stem‐like' properties. In this study, we characterise how the improved culture of adipose‐derived mesenchymal stem cells (ASCs) within a tissue‐mimetic 3D hydrogel system, that is mechanically similar to native adipose tissue, enhances their regenerative capabilities. Notably, the hydrogel system contains a porous microarchitecture that permits mass transport, enabling efficient collection of secreted cellular compounds. By utilising this 3D system, ASCs retained a significantly higher expression of ASC 'stem‐like' markers while demonstrating a significant reduction in senescent populations, relative to 2D. Additionally, culture of ASCs within the 3D system resulted in enhanced secretory activity with significant increases in the secretion of proteinaceous factors, antioxidants and extracellular vesicles (EVs) within the conditioned media (CM) fraction. Lastly, treatment of wound healing cells, keratinocytes (KCs) and fibroblasts (FBs), with ASC‐CM from the 2D and 3D systems resulted in augmented functional regenerative activity, with ASC‐CM from the 3D system significantly increasing KC and FB metabolic, proliferative and migratory activity. This study demonstrates the potential beneficial role of MSC culture within a tissue‐mimetic 3D hydrogel system that more closely mimics native tissue mechanics, and subsequently how the improved phenotype augments secretory activity and potential wound healing capabilities of the MSC secretome. [ABSTRACT FROM AUTHOR]

Emulsion electrospinning provides a tunable system for the development of porous scaffolds for controlled, localized drug delivery in tissue engineering applications. This study aimed to elucidate the role of model drug interactions with emulsion chemistry on loading and release rates from fibers with controlled fiber diameter and fiber volume fraction. Nile Red and Rhodamine B were used as model drugs and encapsulation efficiency and release rates were determined from poly(caprolactone) (PCL) electrospun fibers spun either with no surfactant (Span 80), surfactant, or water‐in‐oil emulsions. Drug loading efficiency and release rates were modulated by both surfactant and aqueous internal phase in the emulsions as a function of drug molecule hydrophobicity. Overall, these results demonstrate the role of intermolecular interactions and drug phase solubility on the release from emulsion electrospun fibers and highlight the need to independently control these parameters when designing fibers for use as tunable drug delivery systems. [ABSTRACT FROM AUTHOR]

Background: To the authors' knowledge, the empiric identification of agents and interventions to mitigate chemotherapy‐induced peripheral neuropathy (CIPN) has resulted in only 1 agent that modestly mitigates it and no agents or interventions that prevent its development. This speaks to the need for a mechanistic understanding of CIPN to develop effective interventions. Methods: To understand the extent to which mechanistic understanding of CIPN is being translated into the development of interventions, the National Cancer Institute conducted a review of the National Institutes of Health (NIH)'s portfolio of investigator‐initiated grants, the literature regarding CIPN mechanisms, and the clinical trials listed in the ClinicalTrials.gov database from January 1, 2011, to May 22, 2019. Results: A total of 69 NIH‐supported grants and 95 published articles were identified that evaluated mechanistic pathways of 7 different chemotherapy agents that cause CIPN. The review also identified 35 clinical trials that investigated agents or devices with which to treat CIPN. Only 3 trials incorporated a mechanistic rationale to support the choice of the intervention. Conclusions: To the authors' knowledge, very little of the mechanistic understanding of the development of CIPN is being translated into intervention rationale in clinical trials that evaluate interventions to mitigate CIPN. Efforts to incentivize this translation are needed. Very little of the mechanistic understanding of the development of chemotherapy‐induced peripheral neuropathy (CIPN) currently is being translated into intervention rationale in clinical trials that evaluate interventions to mitigate CIPN. The integration of different types of research that bridge the gap between preclinical and clinical research is crucial to developing effective interventions to prevent or treat CIPN. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to compare self-reported with objective measurements of energy intake changes (∆EI) during a 1-year weight-loss intervention with subjects randomized to low-carbohydrate versus low-fat diets.Methods: Repeated body weight measurements were used as inputs to an objective mathematical model to calculate ∆EIModel and to compare with self-reported energy intake changes assessed by repeated 24-hour recalls (∆EIRecall ).Results: ∆EIRecall indicated a relatively persistent state of calorie restriction of ~500 to 600 kcal/d at 3, 6, and 12 months with no significant differences between the diets. ∆EIModel demonstrated large early decreases in calorie intake > 800 kcal/d followed by an exponential return to ~100 kcal/d below baseline at the end of the year. Accounting for self-reported physical activities did not materially affect the results. Discrepancies between ∆EIModel and ∆EIRecall became progressively greater over time. The low-carbohydrate diet resulted in ∆EIModel that was 162 ± 53 kcal/d lower than the low-fat diet over the first 3 months (P  =  0.002), but no significant diet differences were found thereafter.Conclusions: Self-reported ∆EI measurements were inaccurate. Model-based calculations of ∆EI found that instructions to follow the low-carbohydrate diet resulted in greater calorie restriction than the low-fat diet in the early phases of the intervention, but these diet differences were not sustained. [ABSTRACT FROM AUTHOR]

Objectives: To review the literature and summarize the evidence of temporomandibualar joint (TMJ) disorders (TMDs) in older adults, focusing on clinical manifestations of TMDs in older adults, highlighting the incidence and sexual dimorphism of TMJ degeneration and the role of sex hormones in this process, and providing potential treatment options for TMD in older adults. Design: Two review authors performed the literature search, study inclusion, and data extraction. PubMed, Embase, and Google scholar were searched for literature until August 2017 (Figure ). We adopted a combination of Medical Subject Headings with related free text words for the search in PubMed and optimized the search in other search engines. Results: Traditionally, it was believed that TMDs predominantly affected women of childbearing age, but recent large studies in Europe and the United States have shown that the prevalence of TMD peaks after childbearing age (45–64) and then gradually decreases with age, although not much is known about the disease in older adults. Conclusion: Most older adults have TMJ degeneration, which affects women more than men. In most older adults, the symptoms of TMD are mild and self‐limiting and can usually be treated with self management. [ABSTRACT FROM AUTHOR]

Objectives Military service members risk acquiring posttraumatic stress disorder (PTSD) and mild-traumatic brain injury (mTBI), with high comorbidity. Owing to overlapping symptomatology in chronic mTBI or postconcussion syndrome (PCS) and PTSD, it is difficult to assess the etiology of a patient's condition without objective measures. Using resting-state functional MRI in a novel framework, we tested the hypothesis that their neural signatures are characterized by functionally hyperconnected brain regions which are less variable over time. Additionally, we predicted that such connectivities possessed the highest ability in predicting the diagnostic membership of a novel subject (top-predictors) in addition to being statistically significant. Methods U.S. Army Soldiers ( N = 87) with PTSD and comorbid PCS + PTSD were recruited along with combat controls. Static and dynamic functional connectivities were evaluated. Group differences were obtained in accordance with our hypothesis. Machine learning classification (MLC) was employed to determine top predictors. Results From whole-brain connectivity, we identified the hippocampus-striatum connectivity to be significantly altered in accordance with our hypothesis. Diffusion tractography revealed compromised white-matter integrity between aforementioned regions only in the PCS + PTSD group, suggesting a structural etiology for the PCS + PTSD group rather than being an extreme subset of PTSD. Employing MLC, connectivities provided worst-case accuracy of 84% (9% more than psychological measures). Additionally, the hippocampus-striatum connectivities were found to be top predictors and thus a potential biomarker of PTSD/mTBI. Conclusions PTSD/mTBI are associated with hippocampal-striatal hyperconnectivity from which it is difficult to disengage, leading to a habit-like response toward episodic traumatic memories, which fits well with behavioral manifestations of combat-related PTSD/mTBI. Hum Brain Mapp 38:2843-2864, 2017. © 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

ABSTRACT Limbic system structures such as the amygdala (AMG) and the hippocampus (HIPP) are involved in affective and cognitive processing. However, because of the limitations in noninvasive technology, absolute concentrations of the neurotransmitters underlying limbic system engagement are not known. Here, we report changes in the concentrations of the neurotransmitters glutamate (Glu) and gamma-aminobutyric acid (GABA) in the HIPP and the AMG of patients with nonlesional temporal lobe epilepsy undergoing surgery for intracranial subdural and depth electrode implantation. We utilized an in-vivo microdialysis technique while subjects were engaged in cognitive tasks with or without emotional content. The performance of an emotion learning task (EmoLearn) was associated with a significant increase in the concentration of glutamate in the HIPP when images with high valence content were processed, as compared to its concentration while processing images with low valence. In addition, significantly decreased levels of glutamate were found in the AMG when images with predominantly low valence content were processed, as compared to its concentration at baseline. The processing of face stimuli with anger/fear content (FaceMatch task) was accompanied with significantly decreased concentrations of GABA in the AMG and HIPP compared to its levels at the baseline. The processing of shapes on the other hand was accompanied with a significantly decreased concentration of the glutamate in the AMG as well as in the HIPP compared to the baseline. Finally, the performance of a nondeclarative memory task (weather prediction task-WPT) was associated with relatively large and opposite changes in the GABA levels compared to the baseline in the AMG (decrease) and the HIPP (increase). These data are relevant for showing an involvement of the amygdala and the hippocampus in emotional processing and provide additional neurochemical clues towards a more refined model of the functional circuitry of the human limbic system. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Much of what was assumed about the functional topography of the hippocampus was derived from a single case study over half a century ago. Given advances in the imaging sciences, a new era of discovery is underway, with potential to transform the understanding of healthy processing as well as the ability to treat disorders. Coactivation-based parcellation, a meta-analytic approach, and ultra-high field, high-resolution functional and structural neuroimaging to characterize the neurofunctional topography of the hippocampus was employed. Data revealed strong support for an evolutionarily preserved topography along the long-axis. Specifically, the left hippocampus was segmented into three distinct clusters: an emotional processing cluster supported by structural and functional connectivity to the amygdala and parahippocampal gyrus, a cognitive operations cluster, with functional connectivity to the anterior cingulate and inferior frontal gyrus, and a posterior perceptual cluster with distinct structural connectivity patterns to the occipital lobe coupled with functional connectivity to the precuneus and angular gyrus. The right hippocampal segmentation was more ambiguous, with plausible 2- and 5-cluster solutions. Segmentations shared connectivity with brain regions known to support the correlated processes. This represented the first neurofunctional topographic model of the hippocampus using a robust, bias-free, multimodal approach. [ABSTRACT FROM AUTHOR]

β-Blockers for LQTS Types 1 and 2. Background: Beta-blockers are the mainstay therapy in patients with the congenital long-QT syndrome (LQTS) types 1 and 2. However, limited data exist regarding the efficacy and limitations of this form of medical management within high-risk subsets of these populations. Methods and Results: Multivariate analysis was carried out to identify age-related gender- and genotype-specific risk factors for cardiac events (comprising syncope, aborted cardiac arrest [ACA] or sudden cardiac death [SCD]) from birth through age 40 years among 971 LQT1 (n = 549) and LQT2 (n = 422) patients from the International LQTS Registry. Risk factors for cardiac events included the LQT1 genotype (HR = 1.49, P = 0.003) and male gender (HR = 1.31, P = 0.04) in the 0–14 years age group; and the LQT2 genotype (HR = 1.67, P < 0.001) and female gender (HR = 2.58, P < 0.001) in the 15–40 years age group. Gender–genotype subset analysis showed enhanced risk among LQT1 males (HR = 1.93, P < 0.001) and LQT2 females (HR = 3.28, P < 0.001) in the 2 respective age groups. Beta-blocker therapy was associated with a significant risk-reduction in high-risk patients, including a 67% reduction (P = 0.02) in LQT1 males and a 71% reduction (P < 0.001) in LQT2 females. Life-threatening events (ACA/SCD) rarely occurred as a presenting symptom among beta-blocker-treated patients. However, high-risk patients who experienced syncope during beta-blocker therapy had a relatively high rate of subsequent ACA/SCD (>1 event per 100 patient-years). Conclusions: The present findings suggest that beta-blocker therapy should be routinely administered to all high-risk LQT1 and LQT2 patients without contraindications as a first line measure, whereas primary defibrillator therapy should be recommended for those who experience syncope during medical therapy. (J Cardiovasc Electrophysiol, Vol. 21, pp. 893-901, August 2010) [ABSTRACT FROM AUTHOR]

Bipolar disorder is associated with persistent declarative memory disturbances, but the neural basis of these deficits is not well understood. We used fMRI to investigate brain activity during performance on a face-name paired associate task, which allows for the dissociation of encoding and recall-related memory processes. Fifteen clinically remitted bipolar I disorder patients and 24 demographically matched healthy comparison subjects were scanned during task performance. At the voxel level, bipolar patients showed reduced cortical activation, relative to controls, in multiple task-related brain regions during encoding. During recognition, bipolar patients under-activated left hippocampal and parahippocampal regions, despite adequate task performance. Region of interest analyses indicated that, during encoding, bipolar patients had greater bilateral dorsolateral prefrontal (DLPFC) activity than healthy subjects. In contrast, during recognition patients showed hypo-activation relative to controls in the right, but not the left, DLPFC. Although hippocampal activity did not differ between groups during encoding, bipolar patients failed to activate hippocampal regions to the same extent as healthy subjects during recognition. Finally, while better task performance was associated with recognition-related hippocampal activity in healthy subjects, bipolar patients showed an inverse relationship between task performance and hippocampal activity. Remitted bipolar patients over-engaged dorsolateral prefrontal regions when learning face-name pairs, but relative hypoactivation in both prefrontal and medial temporal regions during recognition. These findings suggest a neural basis for the long-term memory deficits consistently observed in patients with bipolar disorder; further, as these patterns appear in symptomatically remitted patients, they are unlikely to be an artifact of mood symptoms. Hum Brain Mapp, 2010. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Functional neuroimaging has evolved into an indispensable tool for noninvasively investigating brain function. A recent development of such methodology is the creation of connectivity models for brain regions and related networks, efforts that have been inhibited by notable limitations. We present a new method for ascertaining functional connectivity of specific brain structures using metaanalytic connectivity modeling (MACM), along with validation of our method using a nonhuman primate database. Drawing from decades of neuroimaging research and spanning multiple behavioral domains, the method overcomes many weaknesses of conventional connectivity analyses and provides a simple, automated alternative to developing accurate and robust models of anatomically-defined human functional connectivity. Applying MACM to the amygdala, a small structure of the brain with a complex network of connections, we found high coherence with anatomical studies in nonhuman primates as well as human-based theoretical models of emotive-cognitive integration, providing evidence for this novel method's utility. Hum Brain Mapp, 2010. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Background: We evaluated the risk factors and clinical course of Long QT syndrome (LQTS) in African-American patients. Methods: The study involved 41 African-Americans and 3456 Caucasians with a QTc ≥ 450 ms from the U.S. portion of the International LQTS Registry. Data included information about the medical history and clinical course of the LQTS patients with end points relating to the occurrence of syncope, aborted cardiac arrest, or LQTS-related sudden cardiac death from birth through age 40 years. The statistical analyses involved Kaplan-Meier time to event graphs and Cox regression models for multivariable risk factor evaluation. Results: The QTc was 29 ms longer in African-Americans than Caucasians. Multivarite Cox analyses with adjustment for decade of birth revealed that the cardiac event rate was similar in African-Americans and Caucasians with LQTS and that beta-blockers were equally effective in reducing cardiac events in the two racial groups. Conclusions: The clinical course of LQTS in African-Americans is similar to that of Caucasians with comparable risk factors and benefit from beta-blocker therapy in the two racial groups. Ann Noninvasive Electrocardiol 2010;15(1):73–76 [ABSTRACT FROM AUTHOR]

Background: Type-1 long-QT syndrome (LQT1) is caused by mutations in the KCNQ1 gene. The purpose of this study was to investigate whether KCNQ1 mutations in highly conserved amino acid residues within the voltage-gated potassium channel family are associated with an increased risk of cardiac events. Methods and Results: The study population involved 492 LQT1 patients with 54 missense mutations in the transmembrane region of the KCNQ1 channel. The amino acid sequences of the transmembrane region of 38 human voltage-gated potassium channels were aligned. An adjusted Shannon entropy score for each amino acid residue was calculated ranging from 0 (no conservation) to 1.0 (full conservation). Cox analysis was used to identify independent factors associated with the first cardiac event (syncope, aborted cardiac arrest, or death). Patients were subcategorized into tertiles by their adjusted Shannon entropy scores. The lowest tertile (score 0–0.469; n = 146) was used as a reference group; patients with intermediate tertile scores (0.470–0.665; n = 150) had no increased risk of cardiac events (HR = 1.19, P = 0.42) or aborted cardiac arrest/sudden cardiac death (HR = 1.58, P = 0.26), and those with the highest tertile scores (>0.665; n = 196) showed significantly increased risk of cardiac events (HR = 3.32, P <0.001) and aborted cardiac arrest/sudden cardiac death (HR = 2.62, P = 0.04). The increased risk in patients with the highest conservation scores was independent of QTc, gender, age, and beta-blocker therapy. Conclusions: Mutations in highly conserved amino acid residues in the KCNQ1 gene are associated with a significant risk of cardiac events independent of QTc, gender, and beta-blocker therapy. [ABSTRACT FROM AUTHOR]

Objectives: Bipolar disorder is associated with working memory (WM) impairments that persist during periods of symptomatic remission. However, the neural underpinnings of these deficits are not well understood. Methods: Fifteen clinically remitted bipolar patients and 15 demographically matched healthy controls underwent functional magnetic resonance imaging while performing a novel delayed-non-match-to-sample (DNMS) task. This nonverbal DNMS task involves two conditions, one requiring the organization of existing memory traces (‘familiarity’), and one involving the formation of new memory traces (‘novelty’). These processes are thought to differentially engage the prefrontal cortex and medial temporal lobe, respectively. Results: Although behavioral performance did not differ between groups, bipolar patients and controls exhibited significantly different patterns of neural activity during task performance. Patients showed relative hyperactivation in the right prefrontal gyrus and relative hypoactivation in visual processing regions compared to healthy subjects across both task conditions. During the novelty condition, patients showed a pattern of hypoactivation relative to controls in medial temporal regions, with relative hyperactivation in the anterior cingulate. Conclusions: These findings suggest that disruption in fronto-temporal neural circuitry may underlie memory difficulties frequently observed in patients with bipolar disorder. [ABSTRACT FROM AUTHOR]

Introduction: One form of the hereditary long-QT syndrome, LQT3-ΔKPQ, is associated with sustained inward sodium current during membrane depolarization. Ranolazine reduces late sodium channel current, and we hypothesized that ranolazine would have beneficial effects on electrical and mechanical cardiac function in LQT3 patients with the SCN5A-ΔKPQ mutation. Methods: We assessed the effects of 8-hour intravenous ranolazine infusions (45 mg/h for 3 hours followed by 90 mg/h for 5 hours) on ventricular repolarization and myocardial relaxation in 5 LQT3 patients with the SCN5A-ΔKPQ mutation. Changes in electrocardiographic repolarization parameters from before to during ranolazine infusion were evaluated by time-matched, paired t-test analyses. Cardiac ultrasound recordings were obtained before ranolazine infusion and just before completion of the 8-hour ranolazine infusion. Results: Ranolazine shortened QTc by 26 ± 3 ms (P < 0.0001) in a concentration-dependent manner. At peak ranolazine infusion, there was a significant 13% shortening in left ventricular isovolumic relaxation time, a significant 25% increase in mitral E-wave velocity, and a meaningful 22% decrease in mitral E-wave deceleration time compared with the baseline. No adverse effects of ranolazine were observed in the study patients. Conclusion: Ranolazine at therapeutic concentrations shortened a prolonged QTc interval and improved diastolic relaxation in patients with the LQT3-ΔKPQ mutation, a genetic disorder that is known to cause an increase in late sodium current. [ABSTRACT FROM AUTHOR]

Background: Previous studies of long QT syndrome (LQTS) have focused primarily on the clinical course of affected patients up to 40 years of age to avoid the confounding influence of acquired heart disease on LQTS-related cardiac events in this genetic disorder. Methods: Patients were identified as having coronary disease if they had a history of hospitalization for myocardial infarction, coronary angioplasty, coronary artery bypass graft surgery, or were treated with medication for angina. LQTS-related cardiac events included the first occurrence of syncope, aborted cardiac arrest, or sudden cardiac death without evidence suggestive of an acute coronary event. Cox proportional hazards regression modeling was used to analyze the independent contribution of coronary disease to LQTS-related cardiac events. Results: Time-dependent coronary disease was associated with an increased risk of LQTS-related cardiac events (hazard ratio 2.24, 95% confidence interval 1.23–4.07, P = 0.008) after adjustment for syncopal history before age 40, QTc, and gender. Factors such as diabetes and hypertension that increase the risk for coronary disease were not associated with an increased risk for LQTS-related cardiac events. Conclusions: This is the first study to demonstrate that coronary disease augments the risk for LQTS-related cardiac events in LQTS. The findings highlight the need for more focused preventive therapy in LQTS patients above the age of 40. [ABSTRACT FROM AUTHOR]

Background: Ethnic differences may affect the phenotypic expression of genetic disorders. However, data regarding the effect of ethnicity on outcome in patients with genetic cardiac disorders are limited. We compared the clinical course of Caucasian and Japanese long QT type-1 (LQT1) patients who were matched for mutations in the KCNQ1 gene. Methods: The study population comprised 62 Caucasian and 38 Japanese LQT1 patients from the International LQTS Registry who were identified as having six identical KCNQ1 mutations. The biophysical function of the mutations was categorized into dominant-negative (>50%) or haploinsufficiency (≤50%) reduction in cardiac repolarizing IKs potassium channel current. The primary end point of the study was the occurrence of a first cardiac event from birth through age 40 years. Results: Japanese patients had a significantly higher cumulative rate of cardiac events (67%) than Caucasian patients (39%; P = 0.01). The respective frequencies of dominant negative mutations in the two ethnic groups were 63% and 28% (P < 0.001). In multivariate analysis, Japanese patients had an 81% increase in the risk of cardiac events (P = 0.06) as compared with Caucasians. However, when the biophysical function of the mutations was included in the multivariate model, the risk associated with Japanese ethnicity was no longer evident (HR = 1.05; P = 0.89). Harboring a dominant negative mutation was shown to be the most powerful and significant predictor of outcome (HR = 3.78; P < 0.001). Conclusions: Our data indicate that ethnic differences in the clinical expression of LQTS can be attributed to the differences in frequencies of the specific mutations within the two populations. [ABSTRACT FROM AUTHOR]

Introduction: Data regarding risk factors and clinical course of patients affected with Jervell and Lange-Nielsen syndrome (JLNS), an autosomal recesssive form of the congenital long-QT syndrome (LQTS), are limited to several reported cases and a retrospective analysis. Methods and Results: We prospectively followed-up 44 JLNS patients from the U.S. portion of the International LQTS Registry and compared their clinical course with 2,174 patients with the phenotypically determined dominant form of LQTS (Romano-Ward syndrome [RWS]) and a subgroup of 285 patients with type 1 LQTS (LQT1). Mean (±SD) corrected QT interval (QTc) in the JLNS, RWS, and LQT1 groups were 548 ± 73, 500 ± 48, and 502 ± 46 msec, respectively (P < 0.001). The cumulative rates of cardiac events from birth through age 40 among JLNS and RWS patients were 93% (mean [±SD] age: 5.0 ± 7.0 years) and 54% (mean [±SD] age: 14.2 ± 9.3 years), respectively (P < 0.001). The JLNS:RWS and JLNS:LQT1 adjusted hazard ratios (HR) for cardiac events were highest among patients with a baseline QTc ≥550 msec (HR = 15.83 [P < 0.001] and 13.80 [P < 0.001], respectively). Among JLNS patients treated with beta-blockers, the cumulative probability of LQTS-related death was 35%; defibrillator therapy was associated with a 0% mortality rate during a mean (±SD) follow-up period of 4.9 ± 3.4 years. Conclusions: Patients with JLNS experience a high rate of cardiac and fatal events from early childhood despite medical therapy. Defibrillator therapy appears to improve outcome in this high-risk population, although longer follow-up is needed to establish its long-term efficacy. [ABSTRACT FROM AUTHOR]

Background: We conducted a study of chronic therapy with flecainide versus placebo in a small group of LQT-3 patients with the DeltaKPQ deletion to evaluate the safety and efficacy of flecainide in this genetic disorder. In vitro studies have shown that flecainide provides correction of the impaired inactivation associated with the DeltaKPQ deletion.Methods: A randomized, double-blind, placebo-controlled clinical trial was conducted with flecainide and placebo in six male LQT-3 subjects with the DeltaKPQ deletion.Results: The lowest possible dose of flecainide associated with at least a 40 ms reduction in the QTc interval was determined in an initial open-label, dose-ranging investigation using one-fourth or half of the recommended maximal antiarrhythmic flecainide dose. QTc reduction was achieved with a flecainide dose of 1.5 mg/kg per day in 4 subjects and with 3.0 mg/kg per day in 2 subjects. Subjects were randomized to four 6-month alternating periods of flecainide and placebo therapy based on the open-label dose findings. Average QTc values during placebo and flecainide therapies were 534 ms and 503 ms, respectively, with an adjusted reduction in QTc of -27.1 ms (95% confidence interval: -36.8 ms to -17.4 ms; P<0.001) at a mean flecainide blood level of 0.11+/-0.05 microg/ml. Minimal prolongation in QRS occurred (mean: +2.5 ms), and there were no major adverse cardiac effects.Conclusions: Chronic low-dose flecainide significantly shortens the QTc interval in LQT-3 subjects with the DeltaKPQ mutation. No major adverse drug effects were observed with flecainide during this trial, but the sample size is not large enough to evaluate the safety of flecainide therapy in patients with this mutation. [ABSTRACT FROM AUTHOR]

Background: We conducted a study of chronic therapy with flecainide versus placebo in a small group of LQT-3 patients with the ΔKPQ deletion to evaluate the safety and efficacy of flecainide in this genetic disorder. In vitro studies have shown that flecainide provides correction of the impaired inactivation associated with the ΔKPQ deletion. Methods: A randomized, double-blind, placebo-controlled clinical trial was conducted with flecainide and placebo in six male LQT-3 subjects with the ΔKPQ deletion. Results: The lowest possible dose of flecainide associated with at least a 40 ms reduction in the QTc interval was determined in an initial open-label, dose-ranging investigation using one-fourth or half of the recommended maximal antiarrhythmic flecainide dose. QTc reduction was achieved with a flecainide dose of 1.5 mg/kg per day in 4 subjects and with 3.0 mg/kg per day in 2 subjects. Subjects were randomized to four 6-month alternating periods of flecainide and placebo therapy based on the open-label dose findings. Average QTc values during placebo and flecainide therapies were 534 ms and 503 ms, respectively, with an adjusted reduction in QTc of −27.1 ms (95% confidence interval: −36.8 ms to −17.4 ms; P < 0.001) at a mean flecainide blood level of 0.11 ±0.05 μg/ml. Minimal prolongation in QRS occurred (mean: +2.5 ms), and there were no major adverse cardiac effects. Conclusions: Chronic low-dose flecainide significantly shortens the QTc interval in LQT-3 subjects with the ΔKPQ mutation. No major adverse drug effects were observed with flecainide during this trial, but the sample size is not large enough to evaluate the safety of flecainide therapy in patients with this mutation. [ABSTRACT FROM AUTHOR]

Location of Mutations in LQT1. Introduction: Recent data showed that long QT syndrome (LQTS) patients with mutations in the pore region of the HERG (LQT2) gene have significantly higher risk of cardiac events than subjects with mutations in the non-pore region. The aim of this study was to determine whether there is an association between the location of mutations in the KCNQ1 gene and cardiac events in LQT1 patients. Methods and Results: The study population consisted of 294 LQT1 patients with KCNQ1 gene mutations. Demographic, clinical, and follow-up information was compared among subjects with different locations of KCNQ1 mutations defined as pre-pore region including N-terminus (1–278), pore region (279–354), and post-pore region including C-terminus (>354). Cardiac events observed during follow-up from birth until age of last contact or age 40 years were defined as syncope, cardiac arrest, or sudden death. There were 164 (56%) LQT1 patients with pre-pore mutations, 101 (34%) with pore mutations, and 29 (10%) with post-pore mutations. QTc duration did not differ significantly among the three subgroups (mean QTc = 494, 487, and 501 ms, respectively). There was no significant difference between groups with regard to the risk of cardiac events by age 40 years. Conclusion: There are no significant differences in clinical presentation, ECG parameters, and cardiac events among LQT1 patients with different locations of KCNQ1 mutations. These findings indicate that factors other than location of mutation influence clinical phenotype in patients with LQT1 mutations. (J Cardiovasc Electrophysiol, Vol. 14, pp. 1149-1153, November 2003) [ABSTRACT FROM AUTHOR]

ICD in High-Risk LQTS Patients. Introduction: Implantable cardioverter defibrillators (ICDs) are increasingly being used in high-risk long QT syndrome (LQTS) patients, but there are limited data regarding clinical experience with this therapeutic modality. The aim of this study is to describe the clinical characteristics of 125 LQTS patients treated with ICDs compared with LQTS patients having similar risk indications who were not treated with ICDs. Methods and Results: Among 125 LQTS patients with ICDs, there were 54 cardiac arrest survivors, 19 patients who had ICDs implanted due to recurrent syncope despite beta-blocker therapy, and 52 patients with ICDs implanted due to other reasons, including syncope and LQTS-related sudden death in a close family member. Patients with cardiac arrest and those with recurrent syncope despite beta-blocker therapy (n = 73) were compared to 161 LQTS patients who had similar indications (89 cardiac arrest and 72 recurrent syncope despite beta-blocker therapy) but did not receive ICDs. Total mortality was the endpoint of the analysis. There was 1 (1.3%) death in 73 ICD patients followed an average of 3 years, whereas there were 26 deaths (16%) in non-ICD patients during mean 8-year follow-up (P = 0.07 from log rank test from Kaplan-Meier curves). Conclusion: ICDs provide an important therapeutic option to prevent sudden arrhythmic death in high-risk LQTS patients. A long-term prospective study is needed to determine the benefit of this therapeutic modality in LQTS patients.(J Cardiovasc Electrophysiol, Vol. 14, pp. 337-341, April 2003). [ABSTRACT FROM AUTHOR]

Background: One form of the hereditary long QT syndrome (LQT-3) has recently been shown to be caused by the SCN5A mutation of the human cardiac sodium channel. Cellular studies have suggested that type lb antiarrhythmics may be potentially therapeutic via preferential blockade of the resulting abnormal late inward sodium current. To test this hypothesis, we implemented a pilot study to evaluate the potential for long-term, gene-specific therapy in patients with this disease. Methods and Results: The effects of short-term intravenous lidocaine and oral tocainide were studied in three siblings: two carriers of the SCN5A mutation; and one noncarrier. The two carriers had prolonged QT intervals at baseline, 531 ms, and 566 ms, which markedly shortened with intravenous lidocaine to 438 and 482 ms, respectively. Tocainide-induced correction of the QT interval was similar in both carriers. The noncarrier did not have any significant change in the QT with either drug. One carrier was then placed on outpatient therapy with oral tocainide, and has demonstrated persistent normalization of the QT interval and T wave morphology during the past 10 months. Conclusion: This is the first demonstration of long-term outpatient treatment in LQT-3 using oral tocainide during a 10-month period. QT shortening was achieved by both intravenous lidocaine and oral tocainide, with no adverse affects. The predominant effect was a reduction in the QT onset interval, suggesting that blockade of the mutant sodium current allows repolarization to begin at an earlier time during the action potential. [ABSTRACT FROM AUTHOR]