Catheter ablation of accessory atrioventricular pathways in young patients: Use of long vascular sheaths, the transseptal approach and a retrograde left posterior parallel approach

AbstractObjectives. This study retrospectively assesses the technical aspects of the catheter techniques used to ablate 83 accessory atrioventricular (AV) pathways during 88 procedures in 71 pediatric and adult patients (median age 14 years, range 1 month to 55 years). A number of catheter approaches and techniques evolved that may have improved success and shortened procedure times.Background. Radiofrequency catheter ablation of accessory AV pathways can be highly successful. However, the technical difficulty of many of the procedures is masked by the success rate.Methods. Left free wall, right free wall and septal accessory pathways were ablated with a variety of approaches.Results. Left free wall pathways were ablated successfully by using a standard retrograde approach through the aortic valve in only 10 (24%) of 43 cases. The remaining 33 (76%) required an approach that was either retrograde through the mitral valve (2 of 33), transseptal (21 of 33) or retrograde where the catheter was advanced behind the posterior mitral leaflet at the point of mitral-aortic continuity, so that the catheter course was parallelrather than perpendicularto the mitral anulus (10 of 33). Nineteen of 20 septal pathways were ablated successfully by using either the parallel approach (2 of 29), a transseptal approach (2 of 19), ablation within the coronary sinus or one of its veins (8 of 19) or ablation on the atrial side of the tricuspid valve (7 of 19). Fifteen of 20 right free wall pathways were ablated successfully with a variety of approaches on both the atrial and the ventricular side of the tricuspid valve. Long vascular sheaths were judged to contribute directly to success in 33 (43%) of 77 pathways. The overall success rate has been 93% (77 of 83 pathways), with 100% success for left free wall (43 of 43), 75% for right free wall (15 of 20) and 95% for septal pathways (19 of 20).Conclusions. Thus, successful ablation of accessory AV pathways in a mixed group of pediatric and adult patients appears to benefit from a wide range of vascular and catheter approaches

Functional dynamic genetic effects on gene regulation are specific to particular cell types and environmental conditions

Genetic effects on gene expression and splicing can be modulated by cellular and environmental factors; yet interactions between genotypes, cell type and treatment have not been comprehensively studied together. We used an induced pluripotent stem cell system to study multiple cell types derived from the same individuals and exposed them to a large panel of treatments. Cellular responses involved different genes and pathways for gene expression and splicing, and were highly variable across contexts. For thousands of genes, we identified variable allelic expression across contexts and characterized different types of gene-environment interactions, many of which are associated with complex traits. Promoter functional and evolutionary features distinguished genes with elevated allelic imbalance mean and variance. On average half of the genes with dynamic regulatory interactions were missed by large eQTL mapping studies, indicating the importance of exploring multiple treatments to reveal previously unrecognized regulatory loci that may be important for disease

Functional dynamic genetic effects on gene regulation are specific to particular cell types and environmental conditions

Genetic effects on gene expression and splicing can be modulated by cellular and environmental factors; yet interactions between genotypes, cell type and treatment have not been comprehensively studied together. We used an induced pluripotent stem cell system to study multiple cell types derived from the same individuals and exposed them to a large panel of treatments. Cellular responses involved different genes and pathways for gene expression and splicing, and were highly variable across contexts. For thousands of genes, we identified variable allelic expression across contexts and characterized different types of gene-environment interactions, many of which are associated with complex traits. Promoter functional and evolutionary features distinguished genes with elevated allelic imbalance mean and variance. On average half of the genes with dynamic regulatory interactions were missed by large eQTL mapping studies, indicating the importance of exploring multiple treatments to reveal previously unrecognized regulatory loci that may be important for disease

Glucose Induces Pancreatic Islet Cell Apoptosis That Requires the BH3-Only Proteins Bim and Puma and Multi-BH Domain Protein Bax

OBJECTIVE: High concentrations of circulating glucose are believed to contribute to defective insulin secretion and beta-cell function in diabetes and at least some of this effect appears to be caused by glucose-induced beta-cell apoptosis. In mammalian cells, apoptotic cell death is controlled by the interplay of proapoptotic and antiapoptotic members of the Bcl-2 family. We investigated the apoptotic pathway induced in mouse pancreatic islet cells after exposure to high concentrations of the reducing sugars ribose and glucose as a model of beta-cell death due to long-term metabolic stress. RESEARCH DESIGN AND METHODS: Islets isolated from mice lacking molecules implicated in cell death pathways were exposed to high concentrations of glucose or ribose. Apoptosis was measured by analysis of DNA fragmentation and release of mitochondrial cytochrome c. RESULTS: Deficiency of interleukin-1 receptors or Fas did not diminish apoptosis, making involvement of inflammatory cytokine receptor or death receptor signaling in glucose-induced apoptosis unlikely. In contrast, overexpression of the prosurvival protein Bcl-2 or deficiency of the apoptosis initiating BH3-only proteins Bim or Puma, or the downstream apoptosis effector Bax, markedly reduced glucose- or ribose-induced killing of islets. Loss of other BH3-only proteins Bid or Noxa, or the Bax-related effector Bak, had no impact on glucose-induced apoptosis. CONCLUSIONS: These results implicate the Bcl-2 regulated apoptotic pathway in glucose-induced islet cell killing and indicate points in the pathway at which interventional strategies can be designed

Characterization of the contribution of shared environmental and genetic factors to metabolic syndrome methylation heritability and familial correlations

Abstract Background Transgenerational epigenetic inheritance has been posited as a possible contributor to the observed heritability of metabolic syndrome (MetS). Yet the extent to which estimates of epigenetic inheritance for DNA methylation sites are inflated by environmental and genetic covariance within families is still unclear. We applied current methods to quantify the environmental and genetic contributors to the observed heritability and familial correlations of four previously associated MetS methylation sites at three genes (CPT1A, SOCS3 and ABCG1) using real data made available through the GAW20. Results Our findings support the role of both shared environment and genetic variation in explaining the heritability of MetS and the four MetS cytosine-phosphate-guanine (CpG) sites, although the resulting heritability estimates were indistinguishable from one another. Familial correlations by type of relative pair generally followed our expectation based on relatedness, but in the case of sister and parent pairs we observed nonsignificant trends toward greater correlation than expected, as would be consistent with the role of shared environmental factors in the inflation of our estimated correlations. Conclusions Our work provides an interesting and flexible statistical framework for testing models of epigenetic inheritance in the context of human family studies. Future work should endeavor to replicate our findings and advance these methods to more robustly describe epigenetic inheritance patterns in human populations

Neratinib overcomes trastuzumab resistance in HER2 amplified breast cancer.

Trastuzumab has been shown to improve the survival outcomes of HER2 positive breast cancer patients. However, a significant proportion of HER2-positive patients are either inherently resistant or develop resistance to trastuzumab. We assessed the effects of neratinib, an irreversible panHER inhibitor, in a panel of 36 breast cancer cell lines. We further assessed its effects with or without trastuzumab in several sensitive and resistant breast cancer cells as well as a BT474 xenograft model. We confirmed that neratinib was significantly more active in HER2-amplified than HER2 non-amplified cell lines. Neratinib decreased the activation of the 4 HER receptors and inhibited downstream pathways. However, HER3 and Akt were reactivated at 24 hours, which was prevented by the combination of trastuzumab and neratinib. Neratinib also decreased pHER2 and pHER3 in acquired trastuzumab resistant cells. Neratinib in combination with trastuzumab had a greater growth inhibitory effect than either drug alone in 4 HER2 positive cell lines. Furthermore, trastuzumab in combination with neratinib was growth inhibitory in SKBR3 and BT474 cells which had acquired resistance to trastuzumab as well as in a BT474 xenograft model. Innately trastuzumab resistant cell lines showed sensitivity to neratinib, but the combination did not enhance response compared to neratinib alone. Levels of HER2 and phospho-HER2 showed a direct correlation with sensitivity to neratinib. Our data indicate that neratinib is an effective anti-HER2 therapy and counteracted both innate and acquired trastuzumab resistance in HER2 positive breast cancer. Our results suggest that combined treatment with trastuzumab and neratinib is likely to be more effective than either treatment alone for both trastuzumab-sensitive breast cancer as well as HER2-positive tumors with acquired resistance to trastuzumab

Demographic and sociocultural risk factors for adulthood weight gain in Hispanic/Latinos: results from the Hispanic Community Health Study / Study of Latinos (HCHS/SOL)

Background United States (US) Hispanic/Latinos experience a disproportionate burden of obesity, which may in part be related to demographic or sociocultural factors, including acculturation to an US diet or inactive lifestyle. Therefore, we sought to describe the association between adulthood weight histories and demographic and sociocultural factors in a large diverse community-based cohort of US Hispanic/Latinos. Methods We estimated the effect of several factors on weight gain across adulthood, using multivariable linear mixed models to leverage 38,759 self-reported current body weights and weight histories recalled for 21, 45 and 65 years of age, from 15,203 adults at least 21 years of age at the baseline visit of the Hispanic Community Health Study/Study of Latinos (2008–2011). Results The average rate of weight gain was nearly 10 kg per decade in early adulthood, but slowed to < 5 kg a decade among individuals 60+ years of age. Birth cohort, gender, nativity or age at immigration, Hispanic/Latino background, and study site each significantly modified the form of the predicted adulthood weight trajectory. Among immigrants, weight gain during the 5 years post-migration was on average 0.88 kg (95% CI: 0.04, 1.72) greater than the weight gain during the 5 years prior. The rate of weight gain appeared to slow after 15 years post-migration. Conclusions Using self-reported and weight history data in a diverse sample of US Hispanic/Latinos, we revealed that both demographic and sociocultural factors were associated with the patterning of adulthood weight gain in this sample. Given the steep rate of weight gain in this population and the fact that many Hispanic/Latinos living in the US immigrated as adults, efforts to promote weight maintenance across the life course, including after immigration, should be a top priority for promoting Hispanic/Latino health and addressing US health disparities more broadly

Radio observations of the Black Hole X-ray Binary EXO 1846-031 re-awakening from a 34-year slumber

We present radio [1.3 GHz MeerKAT, 4-8 GHz Karl G. Jansky Very Large Array (VLA) and 15.5 GHz Arcminute Microkelvin Imager Large Array (AMI-LA)] and X-ray (Swift and MAXI) data from the 2019 outburst of the candidate Black Hole X-ray Binary (BHXB) EXO 1846-031. We compute a Hardness-Intensity diagram, which shows the characteristic q-shaped hysteresis of BHXBs in outburst. EXO 1846-031 was monitored weekly with MeerKAT and approximately daily with AMI-LA. The VLA observations provide sub-arcsecond-resolution images at key points in the outburst, showing moving radio components. The radio and X-ray light curves broadly follow each other, showing a peak on ~MJD 58702, followed by a short decline before a second peak between ~MJD 58731-58739. We estimate the minimum energy of these radio flares from equipartition, calculating values of $E_{\rm min} \sim$ 4$\times$10$^{41}$ and 5$\times$10$^{42}$ erg, respectively. The exact date of the return to `quiescence' is missed in the X-ray and radio observations, but we suggest that it likely occurred between MJD 58887 and 58905. From the Swift X-ray flux on MJD 58905 and assuming the soft-to-hard transition happened at 0.3-3 per cent Eddington, we calculate a distance range of 2.4-7.5\,kpc. We computed the radio:X-ray plane for EXO 1846-031 in the `hard' state, showing that it is most likely a `radio-quiet' BH, preferentially at 4.5 kpc. Using this distance and a jet inclination angle of $\theta$=73$^{\circ}$, the VLA data place limits on the intrinsic jet speed of $\beta_{\rm int} = 0.29c$, indicating sub-luminal jet motion.Comment: Accepted for publication in MNRAS on 20 September 2022, 17 pages, 6 figure

The Functional DRD3 Ser9Gly Polymorphism (rs6280) Is Pleiotropic, Affecting Reward as Well as Movement

Abnormalities of motivation and behavior in the context of reward are a fundamental component of addiction and mood disorders. Here we test the effect of a functional missense mutation in the dopamine 3 receptor (DRD3) gene (ser9gly, rs6280) on reward-associated dopamine (DA) release in the striatum. Twenty-six healthy controls (HCs) and 10 unmedicated subjects with major depressive disorder (MDD) completed two positron emission tomography (PET) scans with [11C]raclopride using the bolus plus constant infusion method. On one occasion subjects completed a sensorimotor task (control condition) and on another occasion subjects completed a gambling task (reward condition). A linear regression analysis controlling for age, sex, diagnosis, and self-reported anhedonia indicated that during receipt of unpredictable monetary reward the glycine allele was associated with a greater reduction in D2/3 receptor binding (i.e., increased reward-related DA release) in the middle (anterior) caudate (p<0.01) and the ventral striatum (p<0.05). The possible functional effect of the ser9gly polymorphism on DA release is consistent with previous work demonstrating that the glycine allele yields D3 autoreceptors that have a higher affinity for DA and display more robust intracellular signaling. Preclinical evidence indicates that chronic stress and aversive stimulation induce activation of the DA system, raising the possibility that the glycine allele, by virtue of its facilitatory effect on striatal DA release, increases susceptibility to hyperdopaminergic responses that have previously been associated with stress, addiction, and psychosis