The fully activated open state of KCNQ1 controls the cardiac "fight-or-flight" response.

The cardiac KCNQ1+KCNE1 (I Ks ) channel regulates heart rhythm in both normal and stress conditions. Under stress, the ß-adrenergic stimulation elevates the intracellular cAMP level, leading to KCNQ1 phosphorylation by protein kinase A and increased I Ks , which shortens action potentials to adapt to accelerated heart rate. An impaired response to the ß-adrenergic stimulation due to KCNQ1 mutations is associated with the occurrence of a lethal congenital long QT syndrome (type 1, also known as LQT1). However, the underlying mechanism of ß-adrenergic stimulation of I Ks remains unclear, impeding the development of new therapeutics. Here we find that the unique properties of KCNQ1 channel gating with two distinct open states are key to this mechanism. KCNQ1's fully activated open (AO) state is more sensitive to cAMP than its' intermediate open (IO) state. By enhancing the AO state occupancy, the small molecules ML277 and C28 are found to effectively enhance the cAMP sensitivity of the KCNQ1 channel, independent of KCNE1 association. This finding of enhancing AO state occupancy leads to a potential novel strategy to rescue the response of I Ks to ß-adrenergic stimulation in LQT1 mutants. The success of this approach is demonstrated in cardiac myocytes and also in a high-risk LQT1 mutation. In conclusion the present study not only uncovers the key role of the AO state in I Ks channel phosphorylation, but also provides a new target for anti-arrhythmic strategy. Significance statement: The increase of I Ks potassium currents with adrenalin stimulation is important for "fight-or-flight" responses. Mutations of the IKs channel reducing adrenalin responses are associated with more lethal form of the type-1 long-QT syndrome (LQT). The alpha subunit of the IKs channel, KCNQ1 opens in two distinct open states, the intermediate-open (IO) and activated-open (AO) states, following a two-step voltage sensing domain (VSD) activation process. We found that the AO state, but not the IO state, is responsible for the adrenalin response. Modulators that specifically enhance the AO state occupancy can enhance adrenalin responses of the WT and LQT-associated mutant channels. These results reveal a mechanism of state dependent modulation of ion channels and provide an anti-arrhythmic strategy.

Evaluation of Intracardiac Pressures Using Subharmonic-aided Pressure Estimation with Sonazoid Microbubbles.

Purpose To investigate if the right ventricular (RV) systolic and left ventricular (LV) diastolic pressures can be obtained noninvasively using the subharmonic-aided pressure estimation (SHAPE) technique with Sonazoid microbubbles. Materials and Methods Individuals scheduled for a left and/or right heart catheterization were prospectively enrolled in this institutional review board-approved clinical trial from 2017 to 2020. A standard-of-care catheterization procedure was performed by advancing fluid-filled pressure catheters into the LV and aorta (n = 25) or RV (n = 22), and solid-state high-fidelity pressure catheters into the LV and aorta in a subset of participants (n = 18). Study participants received an infusion of Sonazoid microbubbles (GE HealthCare), and SHAPE data were acquired using a validated interface developed on a SonixTablet (BK Medical) US scanner, synchronously with the pressure catheter data. A conversion factor, derived using cuff-based pressure measurements with a SphygmoCor XCEL PWA (ATCOR) and subharmonic signal from the aorta, was used to convert the subharmonic signal into pressure values. Errors between the pressure measurements obtained using the SHAPE technique and pressure catheter were compared. Results The mean errors in pressure measurements obtained with the SHAPE technique relative to those of the fluid-filled pressure catheter were 1.6 mm Hg ± 1.5 [SD] (P = .85), 8.4 mm Hg ± 6.2 (P = .04), and 7.4 mm Hg ± 5.7 (P = .09) for RV systolic, LV minimum diastolic, and LV end-diastolic pressures, respectively. Relative to the measurements with the solid-state high-fidelity pressure catheter, the mean errors in LV minimum diastolic and LV end-diastolic pressures were 7.2 mm Hg ± 4.5 and 6.8 mm Hg ± 3.3 (P ≥ .44), respectively. Conclusion These results indicate that SHAPE with Sonazoid may have the potential to provide clinically relevant RV systolic and LV diastolic pressures. Keywords: Ultrasound-Contrast, Cardiac, Aorta, Left Ventricle, Right Ventricle ClinicalTrials.gov registration no.: NCT03245255 © RSNA, 2024.

Mechanisms of antiviral action and toxicities of ipecac alkaloids: Emetine and dehydroemetine exhibit anti-coronaviral activities at non-cardiotoxic concentrations.

The emergence of highly infectious pathogens with their potential for triggering global pandemics necessitate the development of effective treatment strategies, including broad-spectrum antiviral therapies to safeguard human health. This study investigates the antiviral activity of emetine, dehydroemetine (DHE), and congeneric compounds against SARS-CoV-2 and HCoV-OC43, and evaluates their impact on the host cell. Concurrently, we assess the potential cardiotoxicity of these ipecac alkaloids. Significantly, our data reveal that emetine and the (-)-R,S isomer of 2,3-dehydroemetine (designated in this paper as DHE4) reduce viral growth at nanomolar concentrations (i.e., IC50 ∼ 50-100 nM), paralleling those required for inhibition of protein synthesis, while calcium channel blocking activity occurs at elevated concentrations (i.e., IC50 ∼ 40-60 µM). Our findings suggest that the antiviral mechanisms primarily involve disruption of host cell protein synthesis and is demonstrably stereoisomer specific. The prospect of a therapeutic window in which emetine or DHE4 inhibit viral propagation without cardiotoxicity renders these alkaloids viable candidates in strategies worthy of clinical investigation.

The association of QTc prolongation with cardiovascular events in cancer patients taking tyrosine kinase inhibitors (TKIs).

OBJECTIVE: To investigate the association between stages of QTc prolongation and the risk of cardiac events among patients on TKIs. METHODS: This was a retrospective cohort study performed at an academic tertiary care center of cancer patients who were taking TKIs or not taking TKIs. Patients with two recorded ECGs between January 1, 2009, and December 31, 2019, were selected from an electronic database. The QTc duration > 450ms was determined as prolonged. The association between QTc prolongation progression and events of cardiovascular disease were compared. RESULTS: This study included a total of 451 patients with 41.2% of patients taking TKIs. During a median follow up period of 3.1 years, 49.5% subjects developed CVD and 5.4% subjects suffered cardiac death in patient using TKIs (n = 186); the corresponding rates are 64.2% and 1.2% for patients not on TKIs (n = 265), respectively. Among patient on TKIs, 4.8% of subjects developed stroke, 20.4% of subjects suffered from heart failure (HF) and 24.2% of subjects had myocardial infarction (MI); corresponding incidence are 6.8%, 26.8% and 30.6% in non-TKIs. When patients were regrouped to TKIs versus non-TKIs with and without diabetes, there was no significant difference in the incidence of cardiac events among all groups. Adjusted Cox proportional hazards models were applied to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). There is a significant increased risk of HF events (HR, 95% CI: 2.12, 1.36-3.32) and MI events (HR, 95% CI: 1.78, 1.16-2.73) during the 1st visit. There are also trends for an increased incidence of cardiac adverse events associated with QTc prolongation among patient with QTc > 450ms, however the difference is not statistically significant. Increased cardiac adverse events in patients with QTc prolongation were reproduced during the 2nd visit and the incidence of heart failure was significantly associated with QTc prolongation(HR, 95% CI: 2.94, 1.73-5.0). CONCLUSION: There is a significant increased QTc prolongation in patients taking TKIs. QTc prolongation caused by TKIs is associated with an increased risk of cardiac events.

Noninvasive Evaluation of Cardiac Chamber Pressures Using Subharmonic-Aided Pressure Estimation With Definity Microbubbles.

BACKGROUND: Noninvasive and accurate assessment of intracardiac pressures has remained an elusive goal of noninvasive cardiac imaging. OBJECTIVES: The purpose of this study was to investigate if errors in intracardiac pressures obtained noninvasively using contrast microbubbles and the subharmonic-aided pressure estimation (SHAPE) technique are <5 mm Hg. METHODS: In a nonrandomized institutional review board-approved clinical trial (NCT03243942), patients scheduled for a left-sided and/or right-sided heart catheterization procedure and providing written informed consent were included. A standard-of-care catheterization procedure was performed advancing clinically used pressure catheters into the left and/or right ventricles and/or the aorta. After pressure catheter placement, patients received an infusion of Definity microbubbles (n = 56; 2 vials diluted in 50 mL of saline; infusion rate: 4-10 mL/min) (Lantheus Medical Imaging). Then SHAPE data was acquired using a validated interface developed on a SonixTablet scanner (BK Medical Systems) synchronously with the pressure catheter data. A conversion factor (mm Hg/dB) was derived from SHAPE data and measurements with a SphygmoCor XCEL PWA device (ATCOR Medical) and was combined with SHAPE data from the left and/or the right ventricles to obtain clinically relevant systolic and diastolic ventricular pressures. RESULTS: The mean value of absolute errors for left ventricular minimum and end diastolic pressures were 2.9 ± 2.0 and 1.7 ± 1.2 mm Hg (n = 26), respectively, and for right ventricular systolic pressures was 2.2 ± 1.5 mm Hg (n = 11). Two adverse events occurred during Definity infusion; both were resolved. CONCLUSIONS: These results indicate that the SHAPE technique with Definity microbubbles is encouragingly efficacious for obtaining intracardiac pressures noninvasively and accurately. (Noninvasive, Subharmonic Intra-Cardiac Pressure Measurement; NCT03243942).

A Consensus-Driven Approach to Redesigning Graduate Medical Education: The Pediatric Anesthesiology Delphi Study.

BACKGROUND: Pediatric anesthesiology fellowship education has necessarily evolved since Accreditation Council for Graduate Medical Education (ACGME) accreditation in 1997. Advancements in perioperative and surgical practices, emerging roles in leadership, increasing mandates by accreditation and certification bodies, and progression toward competency-based education-among other things-have created pressure to enrich the current pediatric anesthesiology training system. The Society for Pediatric Anesthesia (SPA) formed a Task Force for Pediatric Anesthesiology Graduate Medical Education that included key leaders and subject matter experts from the society. A key element of the Task Force's charge was to identify curricular and evaluative enhancements for the fellowship program of the future. METHODS: The Task Force executed a nationally representative, stakeholder-based Delphi process centered around a fundamental theme: "What makes a pediatric anesthesiologist?" to build consensus among a demographically varied and broad group of anesthesiologists within the pediatric anesthesiology community. A total of 37 demographically and geographically varied pediatric anesthesiologists participated in iterative rounds of open- and close-ended survey work between August 2020 and July 2021 to build consensus on the current state, known deficiencies, anticipated needs, and strategies for enhancing national educational offerings and program requirements. RESULTS: Participation was robust, and consensus was almost completely achieved by round 2. This work generated a compelling Strengths, Weaknesses, Opportunities, and Threats (SWOT) analysis that suggests more strengths and opportunities in the current Pediatric Anesthesiology Graduate Medical Education program than weaknesses or threats. Stakeholders agreed that while fellows matriculate with some clinical knowledge and procedural gaps, a few clinical gaps exist upon graduation. Stakeholders agreed on 8 nonclinical domains and specific fundamental and foundational knowledge or skills that should be taught to all pediatric anesthesiology fellows regardless of career plans. These domains include (1) patient safety, (2) quality improvement, (3) communication skills, (4) supervision skills, (5) leadership, (6) medical education, (7) research basics, and (8) practice management. They also agreed that a new case log system should be created to better reflect modern pediatric anesthesia practice. Stakeholders further identified the need for the development of standardized and validated formative and summative assessment tools as part of a competency-based system. Finally, stakeholders noted that significant departmental, institutional, and national organizational support will be necessary to implement the specific recommendations. CONCLUSIONS: A Delphi process achieved robust consensus in assessing current training and recommending future directions for pediatric anesthesiology graduate medical education.

Comparing Central Aortic Pressures Obtained Using a SphygmoCor Device to Pressures Obtained Using a Pressure Catheter.

BACKGROUND: This study compared aortic pressures estimated using a SphygmoCor XCEL PWA device (ATCOR, Naperville, IL) noninvasively with aortic pressures obtained using pressure catheters during catheterization procedures and analyzed the impact of a linear-fit function on the estimated pressure values. METHODS: One hundred and thirty-six patients scheduled for cardiac catheterization procedure were enrolled in IRB approved studies. Catheterization procedures were performed according to standard-of-care to acquire aortic pressure measurements. Immediately after the catheterization procedure with the pressure catheters removed, while the patients were still in the catheterization laboratory, central aortic pressures were estimated with the SphygmoCor device (using its inbuilt transfer function). The error between measured and estimated aortic pressures was evaluated using Bland-Altman analysis (n = 93). A linear-fit was performed between the measured and estimated pressures, and using the linear equation the error measurements were repeated. A bootstrap analysis was performed to test the generalizability of the linear-fit function. In a subset of cases (n = 13), central aortic pressure values were also obtained using solid-state high-fidelity catheters (Millar, Houston, TX), and the error measurements were repeated. RESULTS: The magnitude of errors between the measured and estimated aortic pressures (mean errors >6.4 mm Hg; mean errors >8.0 mm Hg in the subset) were reduced to less than 1 mm Hg after using the linear-fit function derived in this study. CONCLUSIONS: For the population examined in this study, the SphygmoCor data must be used with the linear-fit function to obtain aortic pressures that are comparable to the measurements obtained using pressure catheters. CLINICAL TRIALS REGISTRATION: Trial Numbers NCT03243942 and NCT03245255.

Intercellular delivery of therapeutic oligonucleotides.

One promising approach to cancer therapeutics is to induce changes in gene expression that either reduce cancer cell proliferation or induce cancer cell death. Therefore, delivering oligonucleotides (siRNA/miRNA) that target specific genes or gene programs might have a potential therapeutic benefit. The aim of this study was to examine the potential of cell-based delivery of oligonucleotides to cancer cells via two naturally occurring intercellular pathways: gap junctions and vesicular/exosomal traffic. We utilized human mesenchymal stem cells (hMSCs) as delivery cells and chose to deliver in vitro two synthetic oligonucleotides, AllStars HS Cell Death siRNA and miR-16 mimic, as toxic (therapeutic) oligonucleotides targeting three cancer cell lines: prostate (PC3), pancreatic (PANC1) and cervical (HeLa). Both oligonucleotides dramatically reduced cell proliferation and/or induced cell death when transfected directly into target cells and delivery hMSCs. The delivery and target cells we chose express gap junction connexin 43 (Cx43) endogenously (PC3, PANC1, hMSC) or via stable transfection (HeLaCx43). Co-culture of hMSCs (transfected with either toxic oligonucleotide) with any of Cx43 expressing cancer cells induced target cell death (~20% surviving) or senescence (~85% proliferation reduction) over 96 hours. We eliminated gap junction-mediated delivery by using connexin deficient HeLaWT cells or knocking out endogenous Cx43 in PANC1 and PC3 cells via CRISPR/Cas9. Subsequently, all Cx43 deficient target cells co-cultured with the same toxic oligonucleotide loaded hMSCs proliferated, albeit at significantly slower rates, with cell number increasing on average ~2.2-fold (30% of control cells) over 96 hours. Our results show that both gap junction and vesicular/exosomal intercellular delivery pathways from hMSCs to target cancer cells deliver oligonucleotides and function to either induce cell death or significantly reduce their proliferation. Thus, hMSC-based cellular delivery is an effective method of delivering synthetic oligonucleotides that can significantly reduce tumor cell growth and should be further investigated as a possible approach to cancer therapy.

The Risk of QTc Prolongation in Non-Diabetic and Diabetic Patients Taking Tyrosine Kinase Inhibitors (TKIs)- A Patient Safety Project at a Private Oncology Practice.

Objective: To assess the prevalence of QTc prolongation in both non-diabetic and diabetic patients on TKIs. Some TKIs have been reported to cause QTc prolongation, which is prevalent in diabetes. However, there is no Risk Evaluation and Mitigation Strategy using series ECG to monitor those patients. Methods: Patients taking TKIs, with two ECGs recorded between 1 January 2010 and 31 December 2017 were selected from the electronic database. The QTc duration >450 ms was determined as prolonged. Percentage of QTc prolongation on participants were compared using Chi-Square test. Results: This study included 313 patients (age 66.1 ± 0.8 years and 57.5% are female) taking TKIs. In non-Diabetic patients, the prevalence of QTc prolongation is 19.1% (n = 253) before and 34.8% (n = 253) after treatment with TKIs (p < 0.001), respectively. In diabetic patients, the prevalence of QTc prolongation is 21.7% (n = 60) before and 40% (n = 60) after treatment with TKIs (p = 0.03), respectively. In addition, we examined the effect of modifying risk factors for cardiovascular disease (CVD) on the prevalence of QTc prolongation caused by TKIs. In non-diabetic patients, the prevalence of QTc prolongation is 33.3% (n = 57) before and 34.2% (n = 196) after risk factors modification (p = 0.91), respectively. In diabetic patients, the prevalence of QTc prolongation is 50% (n = 24) before and 33.3% (n = 36) after risk factors modification (p = 0.20), respectively. Conclusion: Use of TKIs is associated with a significantly increased risk of QTc prolongation for patients, particularly when patients are diabetic. Modification of risk factors for CVD does not significantly affect the prevalence of QTc prolongation caused by TKIs.

Acupuncture as an Adjunctive Treatment for Pain in Hospitalized Children With Sickle Cell Disease.

CONTEXT: Acute episodes of pain associated with sickle cell disease (SCD) account for over 100,000 hospitalizations and expenses of nearly one billion dollars annually in the U.S. New treatment approaches are needed as the current opioid based therapy is often inadequate in controlling pain, resulting in prolonged inpatient stays, and high rates of readmission. OBJECTIVES: To evaluate acceptability of acupuncture as an adjunctive therapy and explore the impact of acupuncture on pain related outcomes in a population of youth with SCD hospitalized for management of acute pain. METHODS: This IRB approved single center study recruited youth with SCD (9-20 years) who were hospitalized for management of acute pain into either the acupuncture group or controls. Both groups also received standard pain management therapies. RESULTS: Participants in the acupuncture (n = 19) and control (n = 10) group were comparable in clinical characteristics. Acupuncture had an acceptability rate of over 66% and was tolerated well without any side effects. Acupuncture was associated with reduction in pain scores (6.84-5.51; P < 0.0001). Acupuncture group demonstrated a trend toward lower length of stay and readmission rates, but these were not statistically significant. Opioid use was not different between the groups. Treatment Evaluation Inventory survey showed high rates of satisfaction with acupuncture. CONCLUSION: Acupuncture was broadly accepted and well-tolerated in our study population. Acupuncture treatment was associated with a statistically significant and clinically meaningful reduction in pain scores immediately following the treatments, and a trend towards a reduction in length of stay and readmission for pain.

Modulating the voltage sensor of a cardiac potassium channel shows antiarrhythmic effects.

Cardiac arrhythmias are the most common cause of sudden cardiac death worldwide. Lengthening the ventricular action potential duration (APD), either congenitally or via pathologic or pharmacologic means, predisposes to a life-threatening ventricular arrhythmia, Torsade de Pointes. IKs (KCNQ1+KCNE1), a slowly activating K+ current, plays a role in action potential repolarization. In this study, we screened a chemical library in silico by docking compounds to the voltage-sensing domain (VSD) of the IKs channel. Here, we show that C28 specifically shifted IKs VSD activation in ventricle to more negative voltages and reversed the drug-induced lengthening of APD. At the same dosage, C28 did not cause significant changes of the normal APD in either ventricle or atrium. This study provides evidence in support of a computational prediction of IKs VSD activation as a potential therapeutic approach for all forms of APD prolongation. This outcome could expand the therapeutic efficacy of a myriad of currently approved drugs that may trigger arrhythmias.

Integrative holistic approaches for children, adolescents, and young adults with sickle cell disease: A single center experience.

CONTEXT: Painful vaso-occlusive crises (VOCs) associated with sickle cell disease (SCD) are the most common cause of morbidity, hospitalizations, and poor quality of life. Additional symptoms such as sleep disturbances, fatigue, and stress are also common. Non-traditional approaches are often used by families, but concerns remain that patients may forgo standard of care effective therapies in favor of dangerous unproven alternatives. OBJECTIVES: To describe a single center experience related to a multidisciplinary integrative medicine clinic within the division of hematology dedicated to children and young adults with SCD. METHODS: The Sickle Cell Integrative Clinic at Children's National Hospital services patients with SCD. The main goal of this clinic is to provide access to non-pharmacologic interventions, and to manage patients' symptoms in a holistic manner along with standard of care management of SCD. This IRB approved study evaluated experiences of both patients and parents who attended this clinic. RESULTS: Thirty-seven unique patients attended this clinic over 2 years and 31 participated in the study. After attending the SCD integrative clinic, the majority of patients reported integrative therapies to be an acceptable way of treating pain and believed these to be effective. Overall, the vast majority (88 %) of patients reported having a positive experience with the therapies offered in the clinic. None of the patients experienced any adverse events related to integrative therapies provided in the clinic. CONCLUSION: Our experience suggests that encouraging conversations and offering safe and potentially effective integrative therapies alongside conventional SCD therapies under medical guidance allows patients to have an open discussion about their beliefs and treatment goals, improves patient satisfaction and can improve outcomes.

Regulation of HCN2 Current by PI3K/Akt Signaling.

It has long been known that heart rate is regulated by the autonomic nervous system. Recently, we demonstrated that the pacemaker current, I f , is regulated by phosphoinositide 3-kinase (PI3K) signaling independently of the autonomic nervous system. Inhibition of PI3K in sinus node (SN) myocytes shifts the activation of I f by almost 16 mV in the negative direction. I f in the SN is predominantly mediated by two members of the HCN gene family, HCN4 and HCN1. Purkinje fibers also possess I f and are an important secondary pacemaker in the heart. In contrast to the SN, they express HCN2 and HCN4, while ventricular myocytes, which do not normally pace, express HCN2 alone. In the current work, we investigated PI3K regulation of HCN2 expressed in HEK293 cells. Treatment with the PI3K inhibitor PI-103 caused a negative shift in the activation voltage and a dramatic reduction in the magnitude of the HCN2 current. Similar changes were also seen in cells treated with an inhibitor of the protein kinase Akt, a downstream effector of PI3K. The effects of PI-103 were reversed by perfusion of cells with phosphatidylinositol 3,4,5-trisphosphate (the second messenger produced by PI3K) or active Akt protein. We identified serine 861 in mouse HCN2 as a putative Akt phosphorylation site. Mutation of S861 to alanine mimicked the effects of Akt inhibition on voltage dependence and current magnitude. In addition, the Akt inhibitor had no effect on the mutant channel. These results suggest that Akt phosphorylation of mHCN2 S861 accounts for virtually all of the observed actions of PI3K signaling on the HCN2 current. Unexpectedly, Akt inhibition had no effect on I f in SN myocytes. This result raises the possibility that diverse PI3K signaling pathways differentially regulate HCN-induced currents in different tissues, depending on the isoforms expressed.

A PIP2 substitute mediates voltage sensor-pore coupling in KCNQ activation.

KCNQ family K+ channels (KCNQ1-5) in the heart, nerve, epithelium and ear require phosphatidylinositol 4,5-bisphosphate (PIP2) for voltage dependent activation. While membrane lipids are known to regulate voltage sensor domain (VSD) activation and pore opening in voltage dependent gating, PIP2 was found to interact with KCNQ1 and mediate VSD-pore coupling. Here, we show that a compound CP1, identified in silico based on the structures of both KCNQ1 and PIP2, can substitute for PIP2 to mediate VSD-pore coupling. Both PIP2 and CP1 interact with residues amongst a cluster of amino acids critical for VSD-pore coupling. CP1 alters KCNQ channel function due to different interactions with KCNQ compared with PIP2. We also found that CP1 returned drug-induced action potential prolongation in ventricular myocytes to normal durations. These results reveal the structural basis of PIP2 regulation of KCNQ channels and indicate a potential approach for the development of anti-arrhythmic therapy.

A study of the outward background current conductance gK1, the pacemaker current conductance gf, and the gap junction conductance gj as determinants of biological pacing in single cells and in a two-cell syncytium using the dynamic clamp.

We previously demonstrated that a two-cell syncytium, composed of a ventricular myocyte and an mHCN2 expressing cell, recapitulated most properties of in vivo biological pacing induced by mHCN2-transfected hMSCs in the canine ventricle. Here, we use the two-cell syncytium, employing dynamic clamp, to study the roles of gf (pacemaker conductance), gK1 (background K+ conductance), and gj (intercellular coupling conductance) in biological pacing. We studied gf and gK1 in single HEK293 cells expressing cardiac sodium current channel Nav1.5 (SCN5A). At fixed gf, increasing gK1 hyperpolarized the cell and initiated pacing. As gK1 increased, rate increased, then decreased, finally ceasing at membrane potentials near EK. At fixed gK1, increasing gf depolarized the cell and initiated pacing. With increasing gf, rate increased reaching a plateau, then decreased, ceasing at a depolarized membrane potential. We studied gj via virtual coupling with two non-adjacent cells, a driver (HEK293 cell) in which gK1 and gf were injected without SCN5A and a follower (HEK293 cell), expressing SCN5A. At the chosen values of gK1 and gf oscillations initiated in the driver, when gj was increased synchronized pacing began, which then decreased by about 35% as gj approached 20 nS. Virtual uncoupling yielded similar insights into gj. We also studied subthreshold oscillations in physically and virtually coupled cells. When coupling was insufficient to induce pacing, passive spread of the oscillations occurred in the follower. These results show a non-monotonic relationship between gK1, gf, gj, and pacing. Further, oscillations can be generated by gK1 and gf in the absence of SCN5A.

Triggers of Aggressive Behaviors in Intellectually Disabled Adults and Their Association with Autism, Medical Conditions, Psychiatric Disorders, Age and Sex: A Large-Scale Study.

Aggressive behaviors in those with intellectual disability (ID) and autism (ASD) have been linked to a variety of factors including ID level, age, sex, psychiatric disorders, and medical conditions but these factors have not been studied, in large samples, in terms of how they affect the stimuli that trigger aggression. In this survey of 2243 adults, four triggers of aggression associated with frustration, discomfort, change in the physical/social environment, and defensive reactions were analyzed for their relation to ID level, ASD, age, sex, number of psychiatric diagnoses, sleeping problems, seizures, visual impairment, ear infections and gastrointestinal problems. All four triggers were associated with increasing number of psychiatric disorders, with frustration, discomfort, and change intolerance commonly linked to sleeping problems and ASD. Implications for assessment and intervention are discussed.

Regulation of heart rate and the pacemaker current by phosphoinositide 3-kinase signaling.

Heart rate in physiological conditions is set by the sinoatrial node (SN), the primary cardiac pacing tissue. Phosphoinositide 3-kinase (PI3K) signaling is a major regulatory pathway in all normal cells, and its dysregulation is prominent in diabetes, cancer, and heart failure. Here, we show that inhibition of PI3K slows the pacing rate of the SN in situ and in vitro and reduces the early slope of diastolic depolarization. Furthermore, inhibition of PI3K causes a negative shift in the voltage dependence of activation of the pacemaker current, I F, while addition of its second messenger, phosphatidylinositol 3,4,5-trisphosphate, induces a positive shift. These shifts in the activation of I F are independent of, and larger than, those induced by the autonomic nervous system. These results suggest that PI3K is an important regulator of heart rate, and perturbations in this signaling pathway may contribute to the development of arrhythmias.

Autism Spectrum Disorder Decision Tree Subgroups Predict Adaptive Behavior and Autism Severity Trajectories in Children with ASD.

A recent cross-sectional analysis of PDD Behavior Inventory (PDDBI) data, analyzed with a classification and regression tree algorithm, yielded a decision tree (the Autism Spectrum Disorder-Decision Tree or ASD-DT) that detected three behaviorally distinct ASD subgroups: minimally verbal, verbal, and atypical. These subgroups differed in PDDBI profiles and in factors previously reported to be predictors of autism severity and adaptive behavior trajectories. We retrospectively analyzed trajectories of adaptive skills and autism severity in these subgroups, defined by ASD-DTs calculated from initial evaluation PDDBIs. Results confirmed predictions that each subgroup had distinct trajectories that varied with the type of adaptive behavior assessed suggesting that the ASD-DT has prognostic value that could be helpful for both clinical and research applications.