Incidental TEE finding of aberrant chordae tendineae insertion into the basal septum.

A 65-year-old female with severe mitral regurgitation presenting for mitral valve replacement was found to have a previously undiagnosed aberrant papillary muscle with thickened chordae tendineae inserting into the basal septum during intra-operative TEE. Despite its anatomic location, there was no evidence that the aberrant papillary muscle was contributing to the mitral regurgitation or causing left ventricular outflow tract (LVOT) obstruction. The aberrant papillary muscle was resected during the operation and the patient was separated from cardiopulmonary bypass without complications.

Emery-Dreifuss muscular dystrophy.

Emery-Dreifuss muscular dystrophy (EDMD) is a rare muscular dystrophy, but is particularly important to diagnose due to frequent life-threatening cardiac complications. EDMD classically presents with muscle weakness, early contractures, cardiac conduction abnormalities and cardiomyopathy, although the presence and severity of these manifestations vary by subtype and individual. Associated genes include EMD, LMNA, SYNE1, SYNE2, FHL1, TMEM43, SUN1, SUN2, and TTN, encoding emerin, lamin A/C, nesprin-1, nesprin-2, FHL1, LUMA, SUN1, SUN2, and titin, respectively. The Online Mendelian Inheritance in Man database recognizes subtypes 1 through 7, which captures most but not all of the associated genes. Genetic diagnosis is essential whenever available, but traditional diagnostic tools can help steer the evaluation toward EDMD and assist with interpretation of equivocal genetic test results. Management is primarily supportive, but it is important to monitor patients closely, especially for potential cardiac complications. There is a high potential for progress in the treatment of EDMD in the coming years.

Anesthetic Choice for Percutaneous Transcatheter Closure of the Left Atrial Appendage: A National Anesthesia Clinical Outcomes Registry Analysis.

CONTEXT: Left atrial appendage closure (LAAC) was developed as a novel stroke prevention alternative for patients with atrial fibrillation, particularly for those not suitable for long-term oral anticoagulant therapy. Traditionally, general anesthesia (GA) has been more commonly used primarily due to the necessity of transesophageal echocardiography. AIMS: Compare trends of monitored anesthesia care (MAC) versus GA for percutaneous transcatheter LAAC with endocardial implant and assess for independent variables associated with primary anesthetic choice. SETTINGS AND DESIGN: Multi-institutional data collected from across the United States using the National Anesthesia Clinical Outcomes Registry. MATERIAL AND METHODS: Retrospective data analysis from 2017-2021. STATISTICAL ANALYSIS USED: Independent-sample t tests or Mann-Whitney U tests were used for continuous variables and Chi-square tests or Fisher's exact test for categorical variables. Multivariate logistic regression was used to assess patient and hospital characteristics. RESULTS: A total of 19,395 patients underwent the procedure, and 352 patients (1.8%) received MAC. MAC usage trended upward from 2017-2021 (P < 0.0001). MAC patients were more likely to have an American Society of Anesthesiologists (ASA) physical status of≥ 4 (33.6% vs 22.89%) and to have been treated at centers in the South (67.7% vs 44.2%), in rural locations (71% vs 39.5%), and with lower median annual percutaneous transcatheter LAAC volume (102 vs 153 procedures) (all P < 0.0001). In multivariate analysis, patients treated in the West had 85% lower odds of receiving MAC compared to those in the Northeast (AOR: 0.15; 95% CI 0.03-0.80, P = 0.0261). CONCLUSIONS: While GA is the most common anesthetic technique for percutaneous transcatheter closure of the left atrial appendage, a small, statistically significant increase in MAC occurred from 2017-2021. Anesthetic management for LAAC varies with geographic location.

The optimization of aminooxadiazoles as orally active inhibitors of Cdc7.

A series of aminooxadiazoles was optimized for inhibition of Cdc7. Early lead isoquinoline 1 suffered from modest cell potency (cellular IC50=0.71 µM measuring pMCM2), low selectivity against structurally related kinases, and high IV clearance in rats (CL=18 L/h/kg). Extensive optimization resulted in azaindole 26 (Cdc7 IC50=1.1 nM, pMCM2 IC50=32 nM) that demonstrated robust lowering of pMCM2 in a mouse pharmacodynamic (PD) model when dosed orally. Modifications to improve the pharmacokinetic profile of this series were guided by trapping experiments with glutathione in rat hepatocytes.

FUS-immunoreactive inclusions are a common feature in sporadic and non-SOD1 familial amyotrophic lateral sclerosis.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal disorder of motor neuron degeneration. Most cases of ALS are sporadic (SALS), but about 5 to 10% of ALS cases are familial (FALS). Recent studies have shown that mutations in FUS are causal in approximately 4 to 5% of FALS and some apparent SALS cases. The pathogenic mechanism of the mutant FUS-mediated ALS and potential roles of FUS in non-FUS ALS remain to be investigated. METHODS: Immunostaining was performed on postmortem spinal cords from 78 ALS cases, including SALS (n = 52), ALS with dementia (ALS/dementia, n = 10), and FALS (n = 16). In addition, postmortem brains or spinal cords from 22 cases with or without frontotemporal lobar degeneration were also studied. In total, 100 cases were studied. RESULTS: FUS-immunoreactive inclusions were observed in spinal anterior horn neurons in all SALS and FALS cases, except for those with SOD1 mutations. The FUS-containing inclusions were also immunoreactive with antibodies to TDP43, p62, and ubiquitin. A fraction of tested FUS antibodies recognized FUS inclusions, and specific antigen retrieval protocol appeared to be important for detection of the skein-like FUS inclusions. INTERPRETATION: Although mutations in FUS account for only a small fraction of FALS and SALS, our data suggest that FUS protein may be a common component of the cellular inclusions in non-SOD1 ALS and some other neurodegenerative conditions, implying a shared pathogenic pathway underlying SALS, non-SOD1 FALS, ALS/dementia, and related disorders. Our data also indicate that SOD1-linked ALS may have a pathogenic pathway distinct from SALS and other types of FALS.

Prevalence and characteristics of pain in early and late stages of ALS.

The purpose of this study was to compare pain frequency in early and late stages of ALS and to describe the relationship between pain intensity and functional status. Sixty-four patients in different stages of ALS were asked to complete the Neuropathic Pain Scale and to draw the localization of their pain on a body cartoon. The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) and Forced Vital Capacity (FVC) values were obtained from the medical record. A χ(2) correlation was used to compare the proportion of patients with pain in different stages of ALS. Correlation coefficient was used to describe the relationship between pain intensity and functional status (ALSFRS-R). Pain was reported by about half the patients. Using FVC values, patients were subdivided into early, intermediate and late stage of the disease. There was a negative correlation between pain intensity and functional status. There was no statistically significant difference in the presence of pain among patients in the different stages of ALS. In conclusion, our study showed that pain is common in ALS patients. Although pain intensity did correlate negatively with functional status, as expected, we were surprised to find that pain was also present in the early stages of the disease.

Gastrostomy tube placement by endoscopy versus radiologic methods in patients with ALS: a retrospective study of complications and outcome.

Gastrostomy tube placement for malnutrition and weight loss stabilization occurs in many patients with ALS. We sought to compare the outcome and complications of gastrostomy tube placement by endoscopic (PEG) and multiple radiologic (RIG) methods in ALS patients. A retrospective analysis was conducted on all ALS patients evaluated at Northwestern University who received gastrostomy tubes between January 2009 and March 2012. One hundred and eight gastrostomy tube attempts were made on a total of 100 different patients. Failed gastrostomy tube placement occurred in 15.7% of PEGs and 1.9% of RIGs. Post-procedure aspiration was recognized after 10.5% PEG and 0 RIG attempts. Multivariate analysis revealed a linear increase in risk of post-procedure aspiration for every increase in ALSFRS swallow score. No statistically significant differences in failure or complications were observed when comparing two different methods of RIG (push-type vs. pull-type). Our findings support gastrostomy tube placement by radiographic methods in ALS patients. Gastrostomy tube placement by RIG was more often successful and less often associated with aspiration. Our findings add to the growing body of literature that argues for early gastrostomy tube placement in young patients with prominent bulbar involvement.

AMG 900, a small-molecule inhibitor of aurora kinases, potentiates the activity of microtubule-targeting agents in human metastatic breast cancer models.

Breast cancer is the most prevalent malignancy affecting women and ranks second in cancer-related deaths, in which death occurs primarily from metastatic disease. Triple-negative breast cancer (TNBC) is a more aggressive and metastatic subtype of breast cancer that is initially responsive to treatment of microtubule-targeting agents (MTA) such as taxanes. Recently, we reported the characterization of AMG 900, an orally bioavailable, potent, and highly selective pan-Aurora kinase inhibitor that is active in multidrug-resistant cell lines. In this report, we investigate the activity of AMG 900 alone and in combination with two distinct classes of MTAs (taxanes and epothilones) in multidrug-resistant TNBC cell lines and xenografts. In TNBC cells, AMG 900 inhibited phosphorylation of histone H3 on Ser(10), a proximal substrate of Aurora-B, and induced polyploidy and apoptosis. Furthermore, AMG 900 potentiated the antiproliferative effects of paclitaxel and ixabepilone at low nanomolar concentrations. In mice, AMG 900 significantly inhibited the growth of MDA-MB-231 (F(11); parental), MDA-MB-231 (F(11)) PTX-r (paclitaxel-resistant variant), and DU4475 xenografts. The combination of AMG 900 with docetaxel enhanced tumor inhibition in MDA-MB-231 (F(11)) xenografts compared with either monotherapy. Notably, combining AMG 900 with ixabepilone resulted in regressions of MDA-MB-231 (F(11)) PTX-r xenografts, in which more than 50% of the tumors failed to regrow 75 days after the cessation of drug treatment. These findings suggest that AMG 900, alone and in combination with MTAs, may be an effective intervention strategy for the treatment of metastatic breast cancer and provide potential therapeutic options for patients with multidrug-resistant tumors.

Age of onset of amyotrophic lateral sclerosis is modulated by a locus on 1p34.1.

Amyotrophic lateral sclerosis (ALS) is the third most common adult-onset neurodegenerative disease. Individuals with ALS rapidly progress to paralysis and die from respiratory failure within 3 to 5 years after symptom onset. Epidemiological factors explain only a modest amount of the risk for ALS. However, there is growing evidence of a strong genetic component to both familial and sporadic ALS risk. The International Consortium on Amyotrophic Lateral Sclerosis Genetics was established to bring together existing genome-wide association cohorts and identify sporadic ALS susceptibility and age at symptom onset loci. Here, we report the results of a meta-analysis of the International Consortium on Amyotrophic Lateral Sclerosis Genetics genome-wide association samples, consisting of 4243 ALS cases and 5112 controls from 13 European ancestry cohorts from across the United States and Europe. Eight genomic regions provided evidence of association with ALS, including 9p21.2 (rs3849942, odds ratio [OR] = 1.21; p = 4.41 × 10(-7)), 17p11.2 (rs7477, OR = 1.30; p = 2.89 × 10(-7)), and 19p13 (rs12608932, OR = 1.37, p = 1.29 × 10(-7)). Six genomic regions were associated with age at onset of ALS. The strongest evidence for an age of onset locus was observed at 1p34.1, with comparable evidence at rs3011225 (R(2)(partial) = 0.0061; p = 6.59 × 10(-8)) and rs803675 (R(2)(partial) = 0.0060; p = 6.96 × 10(-8)). These associations were consistent across all 13 cohorts. For rs3011225, individuals with at least 1 copy of the minor allele had an earlier average age of onset of over 2 years. Identifying the underlying pathways influencing susceptibility to and age at onset of ALS may provide insight into the pathogenic mechanisms and motivate new pharmacologic targets for this fatal neurodegenerative disease.

Workshop on programming beta cell development, impairment and regeneration.

Helsingør, the city of Hamlet in Denmark, provided the site for the workshop "Programming Beta Cell Development, Impairment and Regeneration" on October 23-26th, 2011. The same location has held two EASD Islet study group meetings, while the previous three workshops were held in Helsinki, Finland (2003), El Perello, Spain (2006) and Peebles, Scotland (2009). The meeting drew 190 attendees from 12 different countries. There were 37 main oral presentations, and 68 posters covered virtually all aspects of the pancreas and provided a dynamic snapshot of the most interesting areas of current investigation. In addition, six parallel workshops on stem cells, epigenetics, autoimmunity, ß-cell imaging, ß-cell identity, omics in ß-cell research and a panel discussion on "to be or not to be a beta cell" were held. Here, we will review some of the newest highlights and still unanswered questions in the field.

Differential involvement of optineurin in amyotrophic lateral sclerosis with or without SOD1 mutations.

BACKGROUND: Mutations in optineurin have recently been linked to amyotrophic lateral sclerosis (ALS). OBJECTIVE: To determine whether optineurin-positive skeinlike inclusions are a common pathologic feature in ALS, including SOD1 -linked ALS. DESIGN: Clinical case series. SETTING: Academic referral center. SUBJECTS: We analyzed spinal cord sections from 46 clinically and pathologically diagnosed ALS cases and ALS transgenic mouse models overexpressing ALS-linked SOD1 mutations G93A or L126Z. RESULTS: We observed optineurin-immunoreactive skeinlike inclusions in all the sporadic ALS and familial ALS cases without SOD1 mutation, but not in cases with SOD1 mutations or in transgenic mice overexpressing the ALS-linked SOD1 mutations G93A or L126Z. CONCLUSION: The data from this study provide evidence that optineurin is involved in the pathogenesis of sporadic ALS and non- SOD1 familial ALS, thus supporting the hypothesis that these forms of ALS share a pathway that is distinct from that of SOD1-linked ALS.

SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis.

BACKGROUND: The SQSTM1 gene encodes p62, a major pathologic protein involved in neurodegeneration. OBJECTIVE: To examine whether SQSTM1 mutations contribute to familial and sporadic amyotrophic lateral sclerosis (ALS). DESIGN: Case-control study. SETTING: Academic research. Patients  A cohort of 546 patients with familial (n = 340) or sporadic (n = 206) ALS seen at a major academic referral center were screened for SQSTM1 mutations. MAIN OUTCOME MEASURES: We evaluated the distribution of missense, deletion, silent, and intronic variants in SQSTM1 among our cohort of patients with ALS. In silico analysis of variants was performed to predict alterations in p62 structure and function. RESULTS: We identified 10 novel SQSTM1 mutations (9 heterozygous missense and 1 deletion) in 15 patients (6 with familial ALS and 9 with sporadic ALS). Predictive in silico analysis classified 8 of 9 missense variants as pathogenic. CONCLUSIONS: Using candidate gene identification based on prior biological knowledge and the functional prediction of rare variants, we identified several novel SQSTM1 mutations in patients with ALS. Our findings provide evidence of a direct genetic role for p62 in ALS pathogenesis and suggest that regulation of protein degradation pathways may represent an important therapeutic target in motor neuron degeneration.

Riluzole metabolism and CYP1A1/2 polymorphisms in patients with ALS.

Riluzole is the only FDA approved drug for the treatment of amyotrophic lateral sclerosis. Riluzole is assumed to be mainly metabolized by the liver cytochrome CYP1A2 and by the extra-hepatic cytochrome CYP1A1. CYP1A2 and CYP1A1 genetic polymorphisms are known, but their relationship to riluzole metabolism in ALS patients has not been investigated. The aim of this study was to determine whether the polymorphisms of the CYP1A2 and the CYP1A1 genes in ALS patients are associated with riluzole metabolic profiles. Thirty-two patients with a diagnosis of probable or definite ALS and who were on riluzole, participated in the study. Trough and peak plasma riluzole levels were measured using analytical chromatography-mass spectrometry methods. Association of the genotypes of the SNPs spanning the CYP1A1 and CYP1A2 genes (including one SNP in the intergenic region) with mean riluzole peak and trough levels was studied using ANOVA and Tukey's HSD. The mean peak riluzole level was 202+/-111 ng/ml and mean trough level 54.3+/-37.5 ng/ml. Our data do not support any association of the four CYP1A1 and CYP1A2 polymorphisms with the riluzole metabolic profile. In conclusion, genetic variations in CYP1A1 and CYP1A2 genes do not seem to influence riluzole levels. Further work is needed to better understand the genetic regulation of CYP1A enzymes and their role in riluzole metabolism.

Myotonic dystrophy type 1 (DM1) presenting with laryngeal stridor and vocal fold paresis.

Myotonic dystrophy type 1 (DM1) is the most common inherited muscle disorder and may present in numerous ways due to characteristic multisystem involvement. We report a 47-year-old man who presented with an 8-year history of slowly progressive dyspnea and episodic stridor. The laryngeal paresis was documented with videostroboscopy and laryngeal electromyography, and treated with tracheostomy and antimyotonia agents.