The human BLM gene is a member of the Escherichia coli recQ helicase family, which includes the Saccharomyces cerevisiae SGS1 and human WRN genes. Defects in BLM are responsible for the human disease Bloom's syndrome, which is characterized in part by genomic instability and a high incidence of cancer. Here we describe the cloning of rad12 ؉ , which is the fission yeast homolog of BLM and is identical to the recently reported rhq1؉ gene. We showed that rad12 null cells are sensitive to DNA damage induced by UV light and ␥ radiation, as well as to the DNA synthesis inhibitor hydroxyurea. Overexpression of the wild-type rad12 ؉ gene also leads to sensitivity to these agents and to defects associated with the loss of the S-phase and G 2 -phase checkpoint control. We showed genetically and biochemically that rad12 ؉ acts upstream from rad9 ؉ , one of the fission yeast G 2 checkpoint control genes, in regulating exit from the S-phase checkpoint. The physical chromosome segregation defects seen in rad12 null cells combined with the checkpoint regulation defect seen in the rad12 ؉ overproducer implicate rad12 ؉ as a key coupler of chromosomal integrity with cell cycle progression.The fission yeast Schizosaccharomyces pombe undergoes a dose-dependent G 2 delay in response to DNA damage caused by radiation (1, 27). Cells remain arrested at this G 2 checkpoint while DNA damage is repaired, then enter mitosis and resume progression through the cell cycle. Six checkpoint rad genes have been identified in S. pombe: rad1 ϩ , rad3ϩ , rad26 ϩ , and hus1 ϩ (1, 2, 9, 27). Mutations in any of these genes result in almost identical phenotypes. The mutant strains are all sensitive to radiation and to agents which transiently inhibit DNA replication, and all lack the G 2 checkpoint, preventing mitotic entry in the presence of such damage (1, 2, 9, 27). While little is known about G 2 checkpoint genes in humans, homologs of S. pombe rad3 ϩ (4, 5) and rad9 ϩ (19) have recently been isolated. Recent studies have implicated cell cycle gene mutations in causing cancer. It is likely that mutations in genes regulating the G 1 and G 2 checkpoints also have the potential to increase cancer susceptibility.The phenomenon of genomic instability has been firmly established as a crucial step in the genesis of cancer (14,31,33). While genomic instability is seen as a step in the progression of cancer cells, there are also several genetic diseases that lead to genomic instability and, ultimately, to cancer. Among these diseases is the rare autosomal recessive disorder Bloom's syndrome (12). The defective gene in Bloom's syndrome, BLM, encodes a putative DNA helicase that is homologous to the Escherichia coli RecQ and Saccharomyces cerevisiae Sgs1 helicases (11,34). While the BLM and SGS1 proteins contain centrally located helicase domains that are homologous to RecQ, they are much larger than RecQ and show homology, both 5Ј and 3Ј, to the helicase core (26, 35, 37).We describe here the cloning of the fission yeast rad12 ϩ gene, which encodes a helic...

Purpose of reviewAntihyperglycemic therapies including sodium glucose contransporter-2 inhibitors (SGLT2i) and glucagonlike peptide-1 receptor agonists (GLP-1 RA) have been demonstrated to confer significant cardiovascular benefit and reduce future events in patients with type 2 diabetes mellitus (T2DM). However, despite positive data from cardiovascular outcome trials, these therapies remain underutilized in a large proportion of patients who have clinical indications and meet coverage guidelines for their initiation. One of the causes of the observed gap between scientific evidence and clinical cardiology practice is therapeutic hesitancy (otherwise known as therapeutic inertia). The purpose of this review is to discuss the contributors to therapeutic hesitancy in the implementation of these evidence-based therapies and, more importantly, provide pragmatic solutions to address these barriers. Recent findingsRecent studies have demonstrated that clinicians may not initiate cardiovascular protective therapies due to a reluctance to overstep perceived interdisciplinary boundaries, concerns about causing harm due to medication side effects, and a sense of unfamiliarity with the optimal choice of therapy amidst a rapidly evolving landscape of T2DM therapies. SummaryHerein, we describe a multifaceted approach aimed at creating a 'permission to prescribe' culture, developing integrated multidisciplinary models of care, enhancing trainees' experiences in cardiovascular disease prevention, and utilizing technology to motivate change. Taken together, these interventions should increase the implementation of evidence-based therapies and improve the quality of life and cardiovascular outcomes of individuals with T2DM.

Background We present a case of a 83‐year‐old man with a prior history of coronary artery bypass who presented to his family physician with progressive symptoms that raised concern for heart failure exacerbation. A chest X‐ray was performed, which showed a fractured topmost sternal wire in the lateral projection and indicated that the sternal wire had migrated into the anterior mediastinum. An emergent electrocardiogram‐gated flash computed tomography angiography confirmed the location of the fractured wire to be in close proximity to the main pulmonary artery. A discussion of migrated sternal wires with a literature review of cases is provided as well. Aims To present a case of a migrated sternal wire and a literature review. Methods An extensive literature review using pubmed and medline with relevant keywords was preformed. Results 11 known cases of migrated sternal wires with various complications, as detailed in the review table. The mortality rate is low but can be associated with significant morbidity. Discussion Fractured wires are quite common and are usually a benign radiographic finding. However, migration of sternal wires is an extremely rare phenomenon. Only a few reported cases in the literature were sternal wires have migrated beyond the sternum, leading to catastrophic clinical consequences, as detailed in the review table. Conclusion Sternal wire complications secondary to migration beyond the sternum are rare but potentially fatal. Precise wire location and risk assessment with CT are more appropriate when wire location cannot be clearly delineated by plain film radiography.

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