Aveir VR, retrievable leadless pacing in the young.

INTRODUCTION: Successful implantations of the Aveir VR, have been effectively demonstrated in adults; however, there remain limited reports supporting safe and feasible implantation of the Aveir VR in the young population. METHODS: Retrospective, observational study of Aveir VR implantation of young patients (≦21 years old) at UC Davis Medical Center from November 2022 to January 2024 via the internal jugular or femoral vein implantation approaches. Indications for pacing, patient demographics, pacing thresholds and longevity were reported at the time of implantation and last follow-up. RESULTS: A total of 10 patients received the Aveir VR with a median age of years (IQR 12.5-17) and median weight of 50.8 kg (IQR 44.6-60.9) kg. The majority were male (80%). Aveir VR leadless pacemaker occurred via internal jugular venous (90%) or femoral venous (10%) approaches. Indications for placement were intermittent complete heart block (60%) and sinus pauses (40%). Adequate impedance, sensing and thresholds were maintained from implantation to a median follow-up of 9 months. Predicted pacemaker longevity at follow-up median was 23.8 years. There were no complications in any of the 10 patients. CONCLUSION: Aveir VR implantation via the internal jugular and femoral veins is feasible in the young patient population with stable pacing parameters at follow-up.

A Predictive Model for Thiamine Responsive Disorders Among Infants and Young Children: Results from a Prospective Cohort Study in Lao People's Democratic Republic.

OBJECTIVE: To develop a predictive model for thiamine responsive disorders (TRDs) among infants and young children hospitalized with signs or symptoms suggestive of thiamine deficiency disorders (TDDs) based on response to therapeutic thiamine in a high-risk setting. STUDY DESIGN: Children aged 21 days to <18 months hospitalized with signs or symptoms suggestive of TDD in northern Lao People's Democratic Republic were treated with parenteral thiamine (100 mg daily) for ≥3 days in addition to routine care. Physical examinations and recovery assessments were conducted frequently for 72 hours after thiamine was initiated. Individual case reports were independently reviewed by three pediatricians who assigned a TRD status (TRD or non-TRD), which served as the dependent variable in logistic regression models to identify predictors of TRD. Model performance was quantified by empirical area under the receiver operating characteristic curve. RESULTS: A total of 449 children (median [Q1, Q3] 2.9 [1.7, 5.7] months old; 70.3% exclusively/predominantly breastfed) were enrolled; 60.8% had a TRD. Among 52 candidate variables, those most predictive of TRD were exclusive/predominant breastfeeding, hoarse voice/loss of voice, cyanosis, no eye contact, and no diarrhea in the previous 2 weeks. The area under the receiver operating characteristic curve (95% CI) was 0.82 (0.78, 0.86). CONCLUSIONS: In this study, the majority of children with signs or symptoms of TDD responded favorably to thiamine. While five specific features were predictive of TRD, the high prevalence of TRD suggests that thiamine should be administered to all infants and children presenting with any signs or symptoms consistent with TDD in similar high-risk settings. The usefulness of the predictive model in other contexts warrants further exploration and refinement. TRIAL REGISTRATION: Clinicaltrials.gov NCT03626337.

Contemporary Outcomes in Tetralogy of Fallot With Absent Pulmonary Valve After Fetal Diagnosis.

Background Tetralogy of Fallot with absent pulmonary valve is associated with high mortality, but it remains difficult to predict outcomes prenatally. We aimed to identify risk factors for mortality in a large multicenter cohort. Methods and Results Fetal echocardiograms and clinical data from 19 centers over a 10-year period were collected. Primary outcome measures included fetal demise and overall mortality. Of 100 fetuses, pregnancy termination/postnatal nonintervention was elected in 22. Of 78 with intention to treat, 7 (9%) died in utero and 21 (27%) died postnatally. With median follow-up of 32.9 months, no deaths occurred after 13 months. Of 80 fetuses with genetic testing, 46% had chromosomal abnormalities, with 22q11.2 deletion in 35%. On last fetal echocardiogram, at a median of 34.6 weeks, left ventricular dysfunction independently predicted fetal demise (odds ratio [OR], 7.4; 95% CI 1.3, 43.0; P=0.026). Right ventricular dysfunction independently predicted overall mortality in multivariate analysis (OR, 7.9; 95% CI 2.1-30.0; P=0.002). Earlier gestational age at delivery, mediastinal shift, left ventricular/right ventricular dilation, left ventricular dysfunction, tricuspid regurgitation, and Doppler abnormalities were associated with fetal and postnatal mortality, although few tended to progress throughout gestation on serial evaluation. Pulmonary artery diameters did not correlate with outcomes. Conclusions Perinatal mortality in tetralogy of Fallot with absent pulmonary valve remains high, with overall survival of 64% in fetuses with intention to treat. Right ventricular dysfunction independently predicts overall mortality. Left ventricular dysfunction predicts fetal mortality and may influence prenatal management and delivery planning. Mediastinal shift may reflect secondary effects of airway obstruction and abnormal lung development and is associated with increased mortality.

Establishing a case definition of thiamine responsive disorders among infants and young children in Lao PDR: protocol for a prospective cohort study.

INTRODUCTION: Diagnosis of infantile thiamine deficiency disorders (TDD) is challenging due to the non-specific, highly variable clinical presentation, often leading to misdiagnosis. Our primary objective is to develop a case definition for thiamine responsive disorders (TRD) to determine among hospitalised infants and young children, which clinical features and risk factors identify those who respond positively to thiamine administration. METHODS AND ANALYSIS: This prospective study will enrol 662 children (aged 21 days to <18 months) seeking treatment for TDD symptoms. Children will be treated with intravenous or intramuscular thiamine (100 mg daily for a minimum of 3 days) alongside other interventions deemed appropriate. Baseline assessments, prior to thiamine administration, include a physical examination, echocardiogram and venous blood draw for the determination of thiamine biomarkers. Follow-up assessments include physical examinations (after 4, 8, 12, 24, 36, 48 and 72 hours), echocardiogram (after 24 and 48 hours) and one cranial ultrasound. During the hospital stay, maternal blood and breast-milk samples and diet, health, anthropometric and socio-demographic information will be collected for mother-child pairs. Using these data, a panel of expert paediatricians will determine TRD status for use as the dependent variable in logistic regression models. Models identifying predictors of TRD will be developed and validated for various scenarios. Clinical prediction model performance will be quantified by empirical area under the receiver operating characteristic curve, using resampling cross validation. A frequency-matched community-based cohort of mother-child pairs (n=265) will serve as comparison group for evaluation of potential risk factors for TRD. ETHICS AND DISSEMINATION: Ethical approval has been obtained from The National Ethics Committee for Health Research, Ministry of Health, Lao PDR and the Institutional Review Board of the University of California Davis. The results will be disseminated via scientific articles, presentations and workshops with representatives of the Ministry of Health. TRIAL REGISTRATION NUMBER: NCT03626337.

Left Ventricle to Right Atrial Shunt Associated With Ventricular-Atrial Malalignment, Double Outlet Right Atrium, and Subaortic Membrane.

We describe an asymptomatic 7-year-old boy who was taken to the operating room for repair of a subaortic membrane and possible Gerbode's defect. He was found to have a double outlet right atrium associated with an accessory atrioventricular valve in addition to a small atrial septal defect and subaortic membrane. Regurgitant flow through this accessory valve led to the left ventricle to right atrial shunt that was seen on preoperative ECHO. The atrial septal defect was repaired and a baffle was used to isolate blood flow across the accessory valve from the left atrium to the left ventricle. The patient was discharged on postoperative day 4 and has been doing well 2 years postoperatively.

Chest Pain in Pediatrics.

Chest pain in children and adolescents frequently involves referral to a pediatric cardiologist. The etiology of chest pain in pediatrics is broad, and the vast majority of cases are not due to underlying cardiac pathology. However, evaluations are often pursued due to fear about missing a potentially serious cardiac diagnosis, which may lead to sudden cardiac death. The management of these patients can lead to extensive investigations, medical visits, and hospitalizations, which is costly and unnecessary in many cases. This article reviews noncardiac and cardiac etiologies of chest pain, highlights pertinent details of the patient history and physical examination, discusses the evaluation of patients with chest pain, and identifies when referral to a pediatric cardiologist is recommended.

Syncope in Children and Adolescents.

Syncope is an abrupt loss of consciousness and postural tone frequently due to disturbance of the normal autonomic nervous system reflexive mechanisms in regulating peripheral vascular resistance, blood pressure, and heart rate. This leads to a transient decrease in cerebral blood flow. It is a common presenting complaint in children and adolescents. In many cases, there is a characteristic preceding prodrome of dizziness, nausea, diaphoresis, and pallor. Although most cases of syncope are benign in etiology, it frequently causes stress and anxiety in regard to potential cardiovascular disease and possible sudden cardiac death. With careful screening by detailed patient history, comprehensive physical examination, and electrocardiogram (ECG), a significant majority of patients with serious underlying cardiac conditions will be identified. The routine use of echocardiography, ambulatory ECG, tilt-table tests, and exercise stress tests is expensive and frequently of low diagnostic yield. With benign forms of syncope, patient reassurance and education should be the first-line treatment.

Left atrial deformation predicts pulmonary capillary wedge pressure in pediatric heart transplant recipients.

BACKGROUND: Pulmonary capillary wedge pressure (PCWP) is an important indicator in pediatric heart transplant patients, but commonly used noninvasive surrogates, such as ratio of early diastolic mitral inflow velocity to annular velocity (E/E'), have limitations in this population. This study aimed to evaluate the relation of left atrial (LA) peak systolic strain and distensibility with PCWP in pediatric heart transplant recipients. METHODS: Consecutive pediatric heart transplant patients were enrolled at time of cardiac catheterization, with echocardiogram immediately afterward. E/E' ratio at the lateral and medial mitral annulus, peak LA systolic longitudinal strain by speckle tracking, and LA distensibility were measured from echocardiograms and compared to invasively measured PCWP. RESULTS: In 38 patients (11.1 ± 5.8 years old), PCWP correlated with peak LA systolic strain (r = -0.44, P = 0.01) and LA distensibility (r= -0.43, P = 0.02), but not with E/E'. On receiver operating characteristics analysis, LA strain had a higher area under the curve than LA distensibility (0.846 vs. 0.606). LA strain <18.9% had sensitivity 62% and specificity 95%, with likelihood ratio 12.3 for PCWP ≥12. However, LA strain had lower intra-observer and inter-observer reproducibility than distensibility (intra-class correlation coefficients 0.89 and 0.75 vs. 0.93 and 0.90). CONCLUSIONS: Peak LA systolic strain and LA distensibility may be more useful surrogates of left ventricular filling pressure than E/E' in the pediatric heart transplant population, with greater reproducibility of LA distensibility. Longitudinal studies are needed to evaluate which parameters track changes in PCWP and clinical outcome.

CaMKII activity is essential for improvement of memory-related behaviors by chronic rivastigmine treatment.

Because the cholinergic system is down-regulated in the brain of Alzheimer's disease patients, cognitive deficits in Alzheimer's disease patients are significantly improved by rivastigmine treatment. To address the mechanism underlying rivastigmine-induced memory improvements, we chronically treated olfactory bulbectomized (OBX) mice with rivastigmine. The chronic rivastigmine treatments for 12-13 days starting at 10 days after OBX operation significantly improved memory-related behaviors assessed by Y-maze task, novel object recognition task, passive avoidance task, and Barnes maze task, whereas the single rivastigmine treatment failed to improve the memory. Consistent with the improved memory-related behaviors, long-term potentiation in the hippocampal CA1 region was markedly restored by rivastigmine treatments. In immunoblotting analyses, the reductions of calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation and calcium/calmodulin-dependent protein kinase IV (CaMKIV) phosphorylation in the CA1 region in OBX mice were significantly restored by rivastigmine treatments. In addition, phosphorylation of AMPAR subunit glutamate receptor 1 (GluA1) (Ser-831) and cAMP-responsive element-binding protein (Ser-133) as downstream targets of CaMKII and CaMKIV, respectively, in the CA1 region was also significantly restored by chronic rivastigmine treatments. Finally, we confirmed that rivastigmine-induced improvements of memory-related behaviors and long-term potentiation were not obtained in CaMKIIα(+/-) mice. On the other hand, CaMKIV(-/-) mice did not exhibit the cognitive impairments. Taken together, the stimulation of CaMKII activity in the hippocampus is essential for rivastigmine-induced memory improvement in OBX mice.

Utility of a clinical practice guideline in treatment of chylothorax in the postoperative congenital heart patient.

BACKGROUND: Chylothorax after congenital heart surgery is a common complication with associated morbidities, but consensus treatment guidelines are lacking. Variability exists in the duration of medical treatment and timing for surgical intervention. METHODS: After institution of a clinical practice guideline for management of postoperative chylothorax at a single center, pediatric cardiothoracic intensive care unit (ICU) in June 2010, we retrospectively analyzed 2 cohorts of patients: those with chylothorax from January 2008 to May 2010 (early cohort; n=118) and from June 2010 to August 2011 (late cohort; n=45). Data collected included demographics, cardiac surgical procedure, treatments for chylothorax, bloodstream infections, hospital mortality, length of hospitalization, duration of mechanical ventilation, and device utilization. RESULTS: There were no demographic differences between the cohorts. No differences were found in octreotide use or surgical treatments for chylothorax. Significant differences were found in median times to chylothorax diagnosis (9 in early cohort versus 6 days in late cohort, p=0.004), ICU length of stay (18 vs 9 days, p=0.01), hospital length of stay (30 vs 23 days, p=0.005), and total durations of mechanical ventilation (11 vs 5 days, p=0.02), chest tube use (20 vs 14 days, p=0.01), central venous line use (27 vs 15 days, p=0.001), and NPO status (9.5 vs 6 days, p=0.04). CONCLUSIONS: Institution of a clinical practice guideline for treatment of chylothorax after congenital heart surgery was associated with earlier diagnosis, reduced hospital length of stay, mechanical ventilation, and device utilization for these patients.

Application of immunomagnetic particles to enzyme-linked immunosorbent assay (ELISA) for improvement of detection sensitivity of HCG.

This investigation was aimed at using superparamagnetic particles to enzyme-linked immunosorbent assay (SPIO-ELISA) of human chorionic gonadotropin (hCG) to enhance detection sensitivity of hCG. We found that N-(3-dimethyl aminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) was the best cross-linking reagent to link anti hCG α antibody to superparamagnetic particle (SPIO-anti hCG α antibody immunomagnetic particle). To improve the specificity of the assay, a horse radish peroxidase (HRP)-labeled anti-hCG beta monoclonal antibody was used to detect captured hCG using double antibody sandwich ELISA assay. SPIO-ELISA application to determine hCG increased the sensitivity to 1 mIU/mL, which is a level of sensitivity enabling the diagnosis of pregnancy during the early gestational period.

Magnetic particle-linked anti hCG ß antibody for immunoassay of human chorionic gonadotropin (hCG), potential application to early pregnancy diagnosis.

The objective of this study was to develop a magnetic particle-linked monoclonal antibody to hCG ß for immunosorbent assay of human chorionic gonadotropin (hCG) with improved detection sensitivity. Monoclonal antibody against hCG ß was found to be optimally cross-linked to the superparamagnetic particles (SPIO) using EDC and NHS as cross-linking reagents. This superparamagnetic particle-linked monoclonal antibody was able to concentrate hCG from a tested solution for further ELISA assay using horse radish peroxidase-labeled monoclonal antibody against hCG ß. This hybrid technique had greatly decreased the detection limit to 0.1 mIU/mL, making an early detection of pregnancy possible. With an improved sensitivity and simple operation, the magnetic particle-linked anti hCG ß antibody for immunoassay of human chorionic gonadotropin (hCG) has a great potential to supersede the traditional ELISA for pregnancy diagnosis.

Dextromethorphan inhibition of voltage-gated proton currents in BV2 microglial cells.

Dextromethorphan, an antitussive drug, has a neuroprotective property as evidenced by its inhibition of microglial production of pro-inflammatory cytokines and reactive oxygen species. The microglial activation requires NADPH oxidase activity, which is sustained by voltage-gated proton channels in microglia as they dissipate an intracellular acid buildup. In the present study, we examined the effect of dextromethorphan on proton currents in microglial BV2 cells. Dextromethorphan reversibly inhibited proton currents with an IC(50) value of 51.7 µM at an intracellular/extracellular pH gradient of 5.5/7.3. Dextromethorphan did not change the reversal potential or the voltage dependence of the gating. Dextrorphan and 3-hydroxymorphinan, major metabolites of dextromethorphan, and dextromethorphan methiodide were ineffective in inhibiting proton currents. The results indicate that dextromethorphan inhibition of proton currents would suppress NADPH oxidase activity and, eventually, microglial activation.

Antidepressants inhibit proton currents and tumor necrosis factor-α production in BV2 microglial cells.

Proton channels are gated by voltage and pH gradients, and play an important role in the microglial production of pro-inflammatory cytokines, which are known to be suppressed by antidepressants. In the present study we tested the hypothesis that cytokine inhibition by antidepressants is due to an inhibitory action on proton currents by comparing their effects on tumor necrosis factor-α production with the effects on the proton currents in BV2 murine microglial cells. Imipramine, amitriptyline, desipramine and fluoxetine potently and reversibly inhibited proton currents at micromolar concentrations at an intracellular/extracellular pH gradient of 5.5/7.3. Raising extracellular pH to 8.3 sped up the rate and enhanced the extent of block whereas raising intracellular pH to 6.3 reduced the blocking potency of imipramine. These results support a mechanism where the uncharged drug form penetrates the cell membrane, and the charged form blocks the proton channel from the internal side of membrane. This mode of action was corroborated by an experiment with imipraminium, a permanently charged quaternary derivative, which showed far less block compared to imipramine. The lipopolysaccharide-induced release of tumor necrosis factor-α was inhibited by imipramine at concentrations comparable to those inhibiting the proton current. These results support the hypothesis that tumor necrosis factor-α inhibition by imipramine is related to its inhibitory effects on proton channels.

Glutamate-activated chloride channels: Unique fipronil targets present in insects but not in mammals.

Selectivity to insects over mammals is one of the important characteristics for a chemical to become a useful insecticide. Fipronil was found to block cockroach GABA receptors more potently than rat GABA(A) receptors. Furthermore, glutamate-activated chloride channels (GluCls), which are present in cockroaches but not in mammals, were very sensitive to the blocking action of fipronil. The IC(50)s of fipronil block were 30 nM in cockroach GABA receptors and 1600 nM in rat GABA(A) receptors. Moreover, GluCls of cockroach neurons had low IC(50)s for fipronil. Two types of glutamate-induced chloride current were obswerved: desensitizing and non-desensitizing, with fipronil IC(50)s of 800 and 10 nM, respectively. We have developed methods to separately record these two types of GluCls. The non-desensitizing and desensitizing currents were selectively inhibited by trypsin and polyvinylpyrrolidone, respectively. In conclusion, in addition to GABA receptors, GluCls play a crucial role in selectivity of fipronil to insects over mammals. GluCls form the basis for development of selective and safe insecticides.

Nefiracetam activation of CaM kinase II and protein kinase C mediated by NMDA and metabotropic glutamate receptors in olfactory bulbectomized mice.

Aberrant behaviors related to learning and memory in olfactory bulbectomized (OBX) mice have been documented in the previous studies. We reported that the impairment of long-term potentiation (LTP) of hippocampal CA1 regions from OBX mice was associated with down-regulation of CaM kinase II (CaMKII) and protein kinase C (PKC) activities. We now demonstrated that the nootropic drug, nefiracetam, significantly improved spatial reference memory-related behaviors as assessed by Y-maze and novel object recognition task in OBX mice. Nefiracetam also restored hippocampal LTP injured in OBX mice. Nefiracetam treatment restored LTP-induced PKCalpha (Ser657) and NR1 (Ser896) phosphorylation as well as increase in their basal phosphorylation in the hippocampal CA1 region of OBX mice. Likewise, nefiracetam improved LTP-induced CaMKIIalpha (Thr286) autophosphorylation and GluR1 (Ser831) phosphorylation and increased their basal phosphorylation. The enhancement of PKCalpha (Ser657) and CaMKIIalpha (Thr286) autophosphorylation by nefiracetam was inhibited by treatment with (+/-)-alpha-Methyl-(4-carboxyphenyl)glycine and DL-2-Amino-5-phosphonovaleric acid, respectively. The enhancement of LTP induced by nefiracetam is inhibited by treatment with 2-methyl-6-(phenylethynyl)-pyridine, but not by treatment with LY367385, suggesting that metabotropic glutamate receptor 5 (mGluR5) but not mGluR1 is involved in the nefiracetam-induced LTP enhancement. Taken together, nefiracetam ameliorates OBX-induced deficits in memory-related behaviors and impairment of LTP in the hippocampal CA1 region through activation of NMDAR and mGluR5, thereby leading to an increase in activities of CaMKIIalpha (Thr286) and PKCalpha (Ser657), respectively.

Galantamine enhancement of long-term potentiation is mediated by calcium/calmodulin-dependent protein kinase II and protein kinase C activation.

Galantamine, a novel Alzheimer's drug, is known to inhibit acetylcholinesterase activity and potentiate nicotinic acetylcholine receptor (nAChR) in the brain. We previously reported that galantamine potentiates the NMDA-induced currents in primary cultured rat cortical neurons. We now studied the effects of galantamine on long-term potentiation (LTP) in the rat hippocampal CA1 regions. The field excitatory postsynaptic potentials (fEPSPs) were induced by stimulation of the Schaffer collateral/commissural pathways in the hippocampal CA1 region. Treatment with 0.01-10 microM galantamine did not affect the slope of fEPSPs in the CA1 region. Galantamine treatment increased calcium/calmodulin-dependent protein kinase II (CaMKII) and protein kinase Calpha (PKCalpha) activities with a bell-shaped dose-response curve peaked at 1 microM, thereby increasing the phosphorylation of AMPA receptor, myristoylated alanine-rich protein kinase C, and NMDA receptor as downstream substrates of CaMKII and/or PKCalpha. By contrast, galatamine treatment did not affect protein kinase A activity. Consistent with the bell-shaped CaMKII and PKCalpha activation, galantamine treatment enhanced LTP in the hippocampal CA1 regions with the same bell-shaped dose-response curve. Furthermore, LTP potentiation induced by galantamine treatment at 1 microM was closely associated with both CaMKII and PKC activation with concomitant increase in phosphorylation of their downstream substrates except for synapsin I. In addition, the enhancement of LTP by galantamine was accompanied with alpha7-type nAChR activation. These results suggest that galantamine potentiates NMDA receptor-dependent LTP through alpha7-type nAChR activation, by which the postsynaptic CaMKII and PKC are activated.