Predicting, Recognizing, and Treating Right Heart Failure in Patients Undergoing Durable LVAD Therapy.

Despite advancing technology, right heart failure after left ventricular assist device implantation remains a significant source of morbidity and mortality. With the UNOS allocation policy change, a larger proportion of patients proceeding to LVAD are destination therapy and consist of an overall sicker population. Thus, a comprehensive understanding of right heart failure is critical for ensuring the ongoing success of durable LVADs.

Transmethylamine-N-Oxide Is Associated With Diffuse Cardiac Fibrosis in People Living With HIV.

Background People living with HIV are at increased risk of developing diastolic dysfunction, heart failure, and sudden cardiac death, all of which have been characterized by higher levels of myocardial fibrosis. Transmethylamine-N-oxide (TMAO), a dietary gut metabolite, is linked to the development of myocardial fibrosis in animal models. However, it is unclear whether TMAO plays a role in the development of myocardial fibrosis in people living with HIV.

A Rare Case of Carcinoid Constrictive Pericarditis.

We describe a case of atypical carcinoid heart disease. A 62-year-old woman with well-differentiated neuroendocrine tumor metastatic to the liver and lymph nodes presented with recurrent unilateral pleural effusions and lower extremity edema. Multimodality imaging and workup resulted in the diagnosis of carcinoid-related constrictive pericarditis, a rare form of carcinoid heart disease.

Prognostic Implications of Long-Chain Acylcarnitines in Heart Failure and Reversibility With Mechanical Circulatory Support.

Background: Heart failure (HF) is characterized by perturbations in energy homeostasis and metabolism. The reversibility and prognostic value of circulating markers associated with these changes remain unclear.

Objectives: This study sought to describe the metabolomic profiles of patients along the spectrum of systolic HF, determine their association with adverse outcomes in a clinical trial of HF, and evaluate whether identified metabolites change with treatment for end-stage systolic HF.

Giant, completely calcified lumbar juxtafacet cyst: report of an unusual case.

Study Design Case report. Objective To report the case of one patient who developed a giant, completely calcified, juxtafacet cyst. Methods A 57-year-old woman presented with a 2-year history of progressively worsening lower back pain, left leg pain, weakness, and paresthesias.

Representativeness of RELAX-AHF clinical trial population in acute heart failure.

Background: The Relaxin for the Treatment of Acute Heart Failure (RELAX-AHF) trial enrolled 1161 patients admitted to the hospital for acute heart failure (AHF) to evaluate the therapeutic efficacy of serelaxin, a recombinant form of human relaxin-2. We characterized how representative RELAX-AHF clinical trial enrollees were to those patients with AHF found in international registries.

Methods And Results: We examined 196 770 AHF admissions from the Acute Decompensated Heart Failure National Registry-United States and Acute Decompensated Heart Failure National Registry-International registries.

Valvular heart disease in patients supported with left ventricular assist devices.

Patients with advanced HF and coexisting VHD who undergo LVAD implantation constitute a growing population and pose unique challenges in clinical and surgical management. Contemporary continuous-flow LVADs alter blood flow dynamics and cardiovascular physiology and can induce progression of preexisting VHD or lead to de novo VHD. Although we have defined our recommendations for treatment options (Table 2), continued changes to device technology, patient selection, and surgical techniques will undoubtedly lead to further changes in practice.

Drug overdose resulting in quadriplegia.

Purpose: To describe a case of cervical flexion myelopathy resulting from a drug overdose.

Methods: A 56-year-old male presented to the emergency department unable to move his extremities following drug overdose. Neurological examination revealed him to be at C6 ASIA A spinal cord injury.

Replication-compromised cells require the mitotic checkpoint to prevent tetraploidization.

Replication stress often induces chromosome instability. In this study, we explore which factors in replication-compromised cells promote abnormal chromosome ploidy. We expressed mutant forms of either polymerase α (Polα) or polymerase δ (Polδ) in normal human fibroblasts to compromise DNA replication.

Schizosaccharomyces pombe Rtf2 mediates site-specific replication termination by inhibiting replication restart.

Here, we identify a phylogenetically conserved Schizosaccharomyces pombe factor, named Rtf2, as a key requirement for efficient replication termination at the site-specific replication barrier RTS1. We show that Rtf2, a proliferating cell nuclear antigen-interacting protein, promotes termination at RTS1 by preventing replication restart; in the absence of Rtf2, we observe the establishment of "slow-moving" Srs2-dependent replication forks. Analysis of the pmt3 (SUMO) and rtf2 mutants establishes that pmt3 causes a reduction in RTS1 barrier activity, that rtf2 and pmt3 are nonadditive, and that pmt3 (SUMO) partly suppresses the rtf2-dependent replication restart.

Rad3-dependent phosphorylation of the checkpoint clamp regulates repair-pathway choice.

When replication forks collapse, Rad3 phosphorylates the checkpoint-clamp protein Rad9 in a manner that depends on Thr 225, a residue within the PCNA-like domain. The physiological function of Thr 225-dependent Rad9 phosphorylation, however, remains elusive. Here, we show that Thr 225-dependent Rad9 phosphorylation by Rad3 regulates DNA repair pathways.

Rad4TopBP1 associates with Srr2, an Spc1 MAPK-regulated protein, in response to environmental stress.

Rad4(TopBP1) is a scaffold in a protein complex containing both replication proteins and checkpoint proteins and plays essential roles in both replication and checkpoint responses. We have previously identified four novel fission yeast mutants of rad4+(TopBP1) to explore how Rad4(TopBP1), a single protein, can play multiple roles in genomic integrity maintenance. Among the four novel mutants, rad4-c17(TopBP1) is a thermosensitive mutant.

Methods for studying mutagenesis and checkpoints in Schizosaccharomyces pombe.

Mutations in genome caretaker genes can induce genomic instability, which are potentially early events in tumorigenesis. Cells have evolved biological processes to cope with the genomic insults. One is a multifaceted response, termed checkpoint, which is a network of signaling pathways to coordinate cell cycle transition with DNA repair, activation of transcriptional programs, and induction of tolerance of the genomic perturbations.

Rad4TopBP1, a scaffold protein, plays separate roles in DNA damage and replication checkpoints and DNA replication.

Rad4TopBP1, a BRCT domain protein, is required for both DNA replication and checkpoint responses. Little is known about how the multiple roles of Rad4TopBP1 are coordinated in maintaining genome integrity. We show here that Rad4TopBP1 of fission yeast physically interacts with the checkpoint sensor proteins, the replicative DNA polymerases, and a WD-repeat protein, Crb3.

Replication checkpoint kinase Cds1 regulates Mus81 to preserve genome integrity during replication stress.

The replication checkpoint kinase Cds1 preserves genome integrity by stabilizing stalled replication forks. Cds1 targets substrates through its FHA domain. The Cds1 FHA domain interacts with Mus81, a subunit of the Mus81-Eme1 structure-specific endonuclease.

A coordinated temporal interplay of nucleosome reorganization factor, sister chromatin cohesion factor, and DNA polymerase alpha facilitates DNA replication.

DNA replication depends critically upon chromatin structure. Little is known about how the replication complex overcomes the nucleosome packages in chromatin during DNA replication. To address this question, we investigate factors that interact in vivo with the principal initiation DNA polymerase, DNA polymerase alpha (Polalpha).

The B-subunit of DNA polymerase alpha-primase associates with the origin recognition complex for initiation of DNA replication.

The B-subunit (p70/Pol12p) of the DNA polymerase alpha-primase (Polalpha-primase) complex is thought to have a regulatory role in an early stage of S phase. We generated a panel of fission yeast thermosensitive mutants of the B-subunit (termed Spb70) to investigate its role in initiation of DNA replication by genetic and biochemical approaches. Here, we show that the fission yeast Spb70 genetically interacts and coprecipitates with origin recognition complex proteins Orp1/Orc1 and Orp2/Orc2 and primase coupling subunit Spp2/p58.

Checkpoint responses to replication stalling: inducing tolerance and preventing mutagenesis.

Replication mutants often exhibit a mutator phenotype characterized by point mutations, single base frameshifts, and the deletion or duplication of sequences flanked by homologous repeats. Mutation in genes encoding checkpoint proteins can significantly affect the mutator phenotype. Here, we use fission yeast (Schizosaccharomyces pombe) as a model system to discuss the checkpoint responses to replication perturbations induced by replication mutants.

Genomic instability induced by mutations in Saccharomyces cerevisiae POL1.

Mutations of chromosome replication genes can be one of the early events that promote genomic instability. Among genes that are involved in chromosomal replication, DNA polymerase alpha is essential for initiation of replication and lagging-strand synthesis. Here we examined the effect of two mutations in S.

Replication proteins influence the maintenance of telomere length and telomerase protein stability.

We investigated the effects of fission yeast replication genes on telomere length maintenance and identified 20 mutant alleles that confer lengthening or shortening of telomeres. The telomere elongation was telomerase dependent in the replication mutants analyzed. Furthermore, the telomerase catalytic subunit, Trt1, and the principal initiation and lagging-strand synthesis DNA polymerase, Polalpha, were reciprocally coimmunoprecipitated, indicating these proteins physically coexist as a complex in vivo.

Checkpoint activation regulates mutagenic translesion synthesis.

Cells have evolved checkpoint responses to arrest or delay the cell cycle, activate DNA repair networks, or induce apoptosis after genomic perturbation. Cells have also evolved the translesion synthesis processes to tolerate genomic lesions by either error-free or error-prone repair. Here, we show that after a replication perturbation, cells exhibit a mutator phenotype, which can be significantly affected by mutations in the checkpoint elements Cds1 and Rad17 or translesion synthesis polymerases DinB and Polzeta.