Ivabradine as a stabilising anti-arrhythmic agent for multifocal atrial tachycardia.

Multifocal atrial tachycardia has certain electrocardiographic similarities to atrial fibrillation. The mechanism of atrial fibrillation is heterogenous but in some cases may arise from a single ectopic driver with fibrillatory conduction to the rest of the atria. This has led to the speculation that multifocal atrial tachycardia may have a similar mechanistic unifocal site that disperses through the atrium in a fibrillatory pattern. Ivabradine has been reported to be efficacious in an adult with paroxysmal atrial fibrillation as well as in children with junctional or ectopic atrial tachycardias. This is the first report of successfully using ivabradine, a novel anti-arrhythmic If blocking agent, to convert multifocal atrial tachycardia in a 5-month-old critically ill infant to a pattern indicating a single ectopic atrial focus. This allowed the patient's single atrial focus to be ablated with return to sinus rhythm and decannulation from ventriculoarterial extracorporeal membrane oxygenation. This case suggests that multifocal atrial tachycardia may arise from a single automatic focus with downstream fibrillatory conduction to the atria.

An unusual presentation of a large cardiac mass.

We present a case of a large left ventricular capillary haemangioma incidentally discovered in a pre-adolescent patient.

Multi-omics analyses reveal ClpP activators disrupt essential mitochondrial pathways in triple-negative breast cancer.

ClpP activators ONC201 and related small molecules (TR compounds, Madera Therapeutics), have demonstrated significant anti-cancer potential in vitro and in vivo studies, including clinical trials for refractory solid tumors. Though progress has been made in identifying specific phenotypic outcomes following ClpP activation, the exact mechanism by which ClpP activation leads to broad anti-cancer activity has yet to be fully elucidated. In this study, we utilized a multi-omics approach to identify the ClpP-dependent proteomic, transcriptomic, and metabolomic changes resulting from ONC201 or the TR compound TR-57 in triple-negative breast cancer cells. Applying mass spectrometry-based methods of proteomics and metabolomics, we identified ∼8,000 proteins and 588 metabolites, respectively. From proteomics data, 113 (ONC201) and 191 (TR-57) proteins significantly increased and 572 (ONC201) and 686 (TR-57) proteins significantly decreased in this study. Gene ontological (GO) analysis revealed strong similarities between proteins up- or downregulated by ONC201 or TR-57 treatment. Notably, this included the downregulation of many mitochondrial processes and proteins, including mitochondrial translation and mitochondrial matrix proteins. We performed a large-scale transcriptomic analysis of WT SUM159 cells, identifying ∼7,700 transcripts (746 and 1,100 significantly increasing, 795 and 1,013 significantly decreasing in ONC201 and TR-57 treated cells, respectively). Less than 21% of these genes were affected by these compounds in ClpP null cells. GO analysis of these data demonstrated additional similarity of response to ONC201 and TR-57, including a decrease in transcripts related to the mitochondrial inner membrane and matrix, cell cycle, and nucleus, and increases in other nuclear transcripts and transcripts related to metal-ion binding. Comparison of response between both compounds demonstrated a highly similar response in all -omics datasets. Analysis of metabolites also revealed significant similarities between ONC201 and TR-57 with increases in α-ketoglutarate and 2-hydroxyglutaric acid and decreased ureidosuccinic acid, L-ascorbic acid, L-serine, and cytidine observed following ClpP activation in TNBC cells. Further analysis identified multiple pathways that were specifically impacted by ClpP activation, including ATF4 activation, heme biosynthesis, and the citrulline/urea cycle. In summary the results of our studies demonstrate that ONC201 and TR-57 induce highly similar and broad effects against multiple mitochondrial processes required for cell proliferation.

Cocaine-Induced Locomotor Activation Differs Across Inbred Mouse Substrains.

Cocaine use disorders (CUD) are devastating for affected individuals and impose a significant societal burden, but there are currently no FDA-approved therapies. The development of novel and effective treatments has been hindered by substantial gaps in our knowledge about the etiology of these disorders. The risk for developing a CUD is influenced by genetics, the environment and complex interactions between the two. Identifying specific genes and environmental risk factors that increase CUD risk would provide an avenue for the development of novel treatments. Rodent models of addiction-relevant behaviors have been a valuable tool for studying the genetics of behavioral responses to drugs of abuse. Traditional genetic mapping using genetically and phenotypically divergent inbred mice has been successful in identifying numerous chromosomal regions that influence addiction-relevant behaviors, but these strategies rarely result in identification of the causal gene or genetic variant. To overcome this challenge, reduced complexity crosses (RCC) between closely related inbred mouse strains have been proposed as a method for rapidly identifying and validating functional variants. The RCC approach is dependent on identifying phenotypic differences between substrains. To date, however, the study of addiction-relevant behaviors has been limited to very few sets of substrains, mostly comprising the C57BL/6 lineage. The present study expands upon the current literature to assess cocaine-induced locomotor activation in 20 inbred mouse substrains representing six inbred strain lineages (A/J, BALB/c, FVB/N, C3H/He, DBA/2 and NOD) that were either bred in-house or supplied directly by a commercial vendor. To our knowledge, we are the first to identify significant differences in cocaine-induced locomotor response in several of these inbred substrains. The identification of substrain differences allows for the initiation of RCC populations to more rapidly identify specific genetic variants associated with acute cocaine response. The observation of behavioral profiles that differ between mice generated in-house and those that are vendor-supplied also presents an opportunity to investigate the influence of environmental factors on cocaine-induced locomotor activity.

Characterization of TR-107, a novel chemical activator of the human mitochondrial protease ClpP.

We recently described the identification of a new class of small-molecule activators of the mitochondrial protease ClpP. These compounds synthesized by Madera Therapeutics showed increased potency of cancer growth inhibition over the related compound ONC201. In this study, we describe chemical optimization and characterization of the next generation of highly potent and selective small-molecule ClpP activators (TR compounds) and demonstrate their efficacy against breast cancer models in vitro and in vivo. We selected one compound (TR-107) with excellent potency, specificity, and drug-like properties for further evaluation. TR-107 showed ClpP-dependent growth inhibition in the low nanomolar range that was equipotent to paclitaxel in triple-negative breast cancer (TNBC) cell models. TR-107 also reduced specific mitochondrial proteins, including OXPHOS and TCA cycle components, in a time-, dose-, and ClpP-dependent manner. Seahorse XF analysis and glucose deprivation experiments confirmed the inactivation of OXPHOS and increased dependence on glycolysis following TR-107 exposure. The pharmacokinetic properties of TR-107 were compared with other known ClpP activators including ONC201 and ONC212. TR-107 displayed excellent exposure and serum t1/2 after oral administration. Using human TNBC MDA-MB-231 xenografts, the antitumor response to TR-107 was investigated. Oral administration of TR-107 resulted in a reduction in tumor volume and extension of survival in the treated compared with vehicle control mice. ClpP activation in vivo was validated by immunoblotting for TFAM and other mitochondrial proteins. In summary, we describe the identification of highly potent new ClpP agonists with improved efficacy against TNBC, through targeted inactivation of OXPHOS and disruption of mitochondrial metabolism.

Left Ventricular Aneurysm in a Child After Recovering From Dilated Cardiomyopathy.

Left ventricular aneurysms are extremely rare in children. A child developed an aneurysm a year after recovering from idiopathic dilated cardiomyopathy. The initial management was conservative. After several years and due to aneurysm enlargement and other complications, the patient underwent successful aneurysm surgical repair with left ventricular aneurysmorrhaphy. We describe our experience treating this child during the course of this disease.

Lyn regulates creatine uptake in an imatinib-resistant CML cell line.

BACKGROUND: Imatinib mesylate (imatinib) is the first-line treatment for newly diagnosed chronic myeloid leukemia (CML) due to its remarkable hematologic and cytogenetic responses. We previously demonstrated that the imatinib-resistant CML cells (Myl-R) contained elevated Lyn activity and intracellular creatine pools compared to imatinib-sensitive Myl cells. METHODS: Stable isotope metabolic labeling, media creatine depletion, and Na+/K+-ATPase inhibitor experiments were performed to investigate the origin of creatine pools in Myl-R cells. Inhibition and shRNA knockdown were performed to investigate the specific role of Lyn in regulating the Na+/K+-ATPase and creatine uptake. RESULTS: Inhibition of the Na+/K+-ATPase pump (ouabain, digitoxin), depletion of extracellular creatine or inhibition of Lyn kinase (ponatinib, dasatinib), demonstrated that enhanced creatine accumulation in Myl-R cells was dependent on uptake from the growth media. Creatine uptake was independent of the Na+/creatine symporter (SLC6A8) expression or de novo synthesis. Western blot analyses showed that phosphorylation of the Na+/K+-ATPase on Tyr 10 (Y10), a known regulatory phosphorylation site, correlated with Lyn activity. Overexpression of Lyn in HEK293 cells increased Y10 phosphorylation (pY10) of the Na+/K+-ATPase, whereas Lyn inhibition or shRNA knockdown reduced Na+/K+-ATPase pY10 and decreased creatine accumulation in Myl-R cells. Consistent with enhanced uptake in Myl-R cells, cyclocreatine (Ccr), a cytotoxic creatine analog, caused significant loss of viability in Myl-R compared to Myl cells. CONCLUSIONS: These data suggest that Lyn can affect creatine uptake through Lyn-dependent phosphorylation and regulation of the Na+/K+-ATPase pump activity. GENERAL SIGNIFICANCE: These studies identify kinase regulation of the Na+/K+-ATPase as pivotal in regulating creatine uptake and energy metabolism in cells.

Mitochondrial Protease ClpP is a Target for the Anticancer Compounds ONC201 and Related Analogues.

ONC201 is a first-in-class imipridone molecule currently in clinical trials for the treatment of multiple cancers. Despite enormous clinical potential, the mechanism of action is controversial. To investigate the mechanism of ONC201 and identify compounds with improved potency, we tested a series of novel ONC201 analogues (TR compounds) for effects on cell viability and stress responses in breast and other cancer models. The TR compounds were found to be ∼50-100 times more potent at inhibiting cell proliferation and inducing the integrated stress response protein ATF4 than ONC201. Using immobilized TR compounds, we identified the human mitochondrial caseinolytic protease P (ClpP) as a specific binding protein by mass spectrometry. Affinity chromatography/drug competition assays showed that the TR compounds bound ClpP with ∼10-fold higher affinity compared to ONC201. Importantly, we found that the peptidase activity of recombinant ClpP was strongly activated by ONC201 and the TR compounds in a dose- and time-dependent manner with the TR compounds displaying a ∼10-100 fold increase in potency over ONC201. Finally, siRNA knockdown of ClpP in SUM159 cells reduced the response to ONC201 and the TR compounds, including induction of CHOP, loss of the mitochondrial proteins (TFAM, TUFM), and the cytostatic effects of these compounds. Thus, we report that ClpP directly binds ONC201 and the related TR compounds and is an important biological target for this class of molecules. Moreover, these studies provide, for the first time, a biochemical basis for the difference in efficacy between ONC201 and the TR compounds.

Progressive Compromise of Nouns and Action Verbs in Posterior Cortical Atrophy.

Processing of nouns and action verbs can be differentially compromised following lesions to posterior and anterior/motor brain regions, respectively. However, little is known about how these deficits progress in the course of neurodegeneration. To address this issue, we assessed productive lexical skills in a patient with posterior cortical atrophy (PCA) at two different stages of his pathology. On both occasions, he underwent a structural brain imaging protocol and completed semantic fluency tasks requiring retrieval of animals (nouns) and actions (verbs). Imaging results were compared with those of controls via voxel-based morphometry (VBM), whereas fluency performance was compared to age-matched norms through Crawford's t-tests. In the first assessment, the patient exhibited atrophy of more posterior regions supporting multimodal semantics (medial temporal and lingual gyri), together with a selective deficit in noun fluency. Then, by the second assessment, the patient's atrophy had progressed mainly toward fronto-motor regions (rolandic operculum, inferior and superior frontal gyri) and subcortical motor hubs (cerebellum, thalamus), and his fluency impairments had extended to action verbs. These results offer unprecedented evidence of the specificity of the pathways related to noun and action-verb impairments in the course of neurodegeneration, highlighting the latter's critical dependence on damage to regions supporting motor functions, as opposed to multimodal semantic processes.

Postoperative complications among octogenarians after cardiovascular surgery.

BACKGROUND: The octogenarian patient is often perceived as too fragile to undergo cardiothoracic surgery. Our study aimed to compare postoperative complications in patients aged less than 80 versus elderly patients (80 years or more) after surgical cardiac intervention (coronary artery bypass or valve replacement). METHODS: Subjects were all patients (n = 8,361) who had an open-heart procedure, either coronary artery bypass or valve implantation or replacement, at two medical centers located in northern Virginia using the same surgical group. A computerized medical record database was reviewed to determine preoperative risk factors and postoperative outcomes. Predictors of complications were identified by univariate and multivariate logistic regression. RESULTS: A total of 3,214 complications were recorded. The most prevalent complications were prolonged ventilation time in the intensive care unit, reoperation for bleeding, and pneumonia. The overall mortality rate was 2.4% (204 of 8,361). Persons aged over 80 years had nearly double the mortality rate compared with younger patients (4.1% [18 of 444] to 2.3% [186 of 7,917]). Age greater than 80 years (odds ratio = 2.65, 95% confidence interval = 2.18 to 3.22) and male gender (odds ratio = 0.62, 95% confidence interval = 0.56 to 0.69) were the best univariate predictors of a single postoperative complication. CONCLUSIONS: Octogenarian patients manifested twice the risk of death from a cardiac intervention with an average 2-day longer hospital stay compared with their younger counterparts. Furthermore, octogenarians were at markedly higher risk of nonfatal postoperative complications.

Combined heart transplantation and thoracic endovascular aortic repair for heart failure secondary to tricuspid atresia palliated with Potts shunt.

A 57-year-old-man with known tricuspid atresia previously palliated with a Potts shunt had developed progressive heart failure refractory to medical management. He underwent a combined thoracic endovascular stent graft procedure to eliminate the Potts shunt and orthotopic heart transplantation. At 3-month follow-up, right-sided heart function and pulmonary artery pressures as well as pulmonary vascular resistance had normalized, and at 7 months, the patient had returned to normal activity. The surgical management and its principles as well as postoperative follow-up are described.

Thoracic esophageal perforations.

BACKGROUND: Recognition of the importance of early diagnosis and aggressive, definitive surgical intervention has brought about a dramatic decline in mortality related to distal esophageal perforation. METHODS: We retrospectively analyzed all cases of thoracic esophageal perforation diagnosed at our hospital from September 1, 1979, through April 1, 2001. The study group consisted of 62 patients (43 men) with a mean age of 58.8 years (range, 20-92 yr). RESULTS: In the group of 39 patients with early diagnosis (< or = 24 h), hospital survival was 87%, which increased to 93% when early diagnosis was combined with aggressive surgical treatment Among the 23 patients with late diagnosis (> 24 h), survival approached 70%. Yet, in patients who were treated aggressively with surgery, survival was almost 90% despite delayed diagnosis. CONCLUSION: We recommend aggressive, definitive surgery for thoracic esophageal perforations, whether diagnosed early or late. A variety of options are discussed with regard to complicated presentations.

Inmunidad celular y humoral en niños con hepatitis B / Cellular and humoral immunity in children with hepatitis B

Se determinaron las poblaciones linfocitarias T por las pruebas de rosetas activas (RA) y espontáneas (RE) y los anticuerpos monoclonales IOR T3 (CD3), IOR T4 (CD4), IOR T8 (CD8), así como el análisis del índice T4/T8 en 49 niños con infección del virus B: 24 pacientes presentaban este virus y 25 el de hepatitis crónica; se incluyen además, 10 niños sanos como grupo control. Se observó diferencia significativa de las rosetas activas entre grupos de estudio y con respecto al control. Las subpoblaciones linfoides en los grupos que se estudiaron no presentaron diferencias en relación con el control, aunque el índice T4/T8 resultó inferior en los de hepatitis crónica. Los inmunocomplejos séricos aumentaron con una mayor proporción en aquellos pacientes con daño hepático

Adecuación del suministro de energía y nutrientes en enfermos con estomatitis aftosa recurrente / Matching energy and nutrient supply in patient with recurrent aphthous stomatitis

Se estudia el grado de adecuación del suministro de energía y 12 nutrientes en una muestra de enfermos con estomatitis aftosa recurrente. Ninguno de los pacientes estudiados tuvo un suministro adecuado de energía, el 95 % de éstos no satisfacía las necesidades de piridoxina y cinc, mientras que el 90 y el 85 % no cubrían las necesidades de ácido fólico y proteína, respectivamente. Asimismo, un número importante de enfermos no alcanzó cumplimentar los requerimientos de tiamina, vitamina A y vitamina E

Estudio de sub-poblaciones linfocitarias mediante anticuerpos monoclonales en hepatitis aguda A y B / Studies of lynphocyte subpopulations with monoclonal antibodies in acute hepatitis

Se determinaron las poblaciones linfocitarias T3, T4 y T8 en sangre periférica con anticuerpos monoclonales en 40 pacientes con hepatitis viral aguda ( 20 de tipo A y 20 de tipo B ), que evolucionaron a la curación. Loa resultados se comparan con los de un grupo control constituído por 20 personas sanas. En ambos tipos de hepatitis se apreció una disminución no significativa del total de linfocitos medidos por el anticuerpo monoclonal T3. Los linfocitos T8 estaban aumentados significativamente ( p menor que 0.05 ) con respecto a los controles, en ambas entidades y el cociente T4/T8 estuvo disminuído en la etapa inicial ( p menor que 0.05 ). No se apreciaron diferencias entre ambos tipos de hepatitis. En el seguimiento evolutivo de los pacientes los valores de estas variables tendieron hacia la normalidad

Adecuación del suministro de energía y nutrientes en enfermos con estomatitis aftosa recurrente / Matching energy and nutrient supply in patient with recurrent aphthous stoatitis

Se estudia el grado de adecuación del suministro de energía y 12 nutrientes en una muestra de enfermos con estomatitis aftosa recurrente. Ninguno de los pacientes estudiados tuvo un suministro adecuado de energía, el 95

de éstos no satisfacía las necesidades de piridoxina y cinc, mientras que el 90 y el 85

no cubrían las necesidades de ácido fólico y proteína, respectivamente. Asimismo, un número importante de enfermos no alcanzó cumplimentar los requerimientos de tiamina, vitamina A y vitamina E

Valoración de posibles factores de la estomatitis aftosa recurrente / Appraisement of possible factors of recurrent aphtous stomatitis

Con el objetivo de valorar los posibles factores etiopatogénicos de la estomatitis aftosa recurrente (EAR), se estudiaron 85 pacientes, 50 mujeres y 35 hombres a los cuales se les realizó drenaje biliar y/o frotis de la mucosa intestinal en búsqueda de giardiasis; también se les realizó estudio inmunológico (cuantificación de linfocitos T, inmunocomplejos séricos y prueba de fagocitosis, así como pruebas psicológicas: inventario multifacético de personalidad de Minnesota (MMPI) y escala de cambios de vida. En el 95,2 % de los casos se demostró la presencia de trofozoitos de Giardia lamblia así como la disminución de los linfocitos t en sangre periférica y un incremento de los inmunocomplejos séricos (p < 0,05). La pruebas psicológicas demostraron un perfil neurótico de menor intensidad así como situaciones previas aa la presencia de las lesiones bucales, valoradas subjetivamente por los pacientes como altamente estresantes. en un alto porcentaje de casos con recidivas se detectaron deficiencias nutricionales y energéticas

Inmunidad celular y humoral en niños con hepatitis B / Cellular and humoral immunity in children with hepatitis B

Se determinaron las poblaciones linfocitarias T por las pruebas de rosetas activas (RA) y espontáneas (RE) y los anticuerpos monoclonales IOR T3 (CD3), IOR T4 (CD4), IOR T8 (CD8), así como el análisis del índice T4/T8 en 49 niños con infección del virus B: 24 pacientes presentaban este virus y 25 el de hepatitis crónica; se incluyen además, 10 niños sanos como grupo control. Se observó diferencia significativa de las rosetas activas entre grupos de estudio y con respecto al control. Las subpoblaciones linfoides en los grupos que se estudiaron no presentaron diferencias en relación con el control, aunque el índice T4/T8 resultó inferior en los de hepatitis crónica. Los inmunocomplejos séricos aumentaron con una mayor proporción en aquellos pacientes con daño hepático