Chest Pain Evaluation: Diagnostic Testing.

Chest pain/discomfort (CP) is a common symptom and can be a diagnostic dilemma for many clinicians. The misdiagnosis of an acute or progressive chronic cardiac etiology may carry a significant risk of morbidity and mortality. This review summarizes the different options and modalities for establishing the diagnosis and severity of coronary artery disease. An effective test selection algorithm should be individually tailored to each patient to maximize diagnostic accuracy in a timely fashion, determine short- and long-term prognosis, and permit implementation of evidence-based treatments in a cost-effective manner. Through collaboration, a decision algorithm was developed (www.chowmd.ca/cadtesting) that could be adopted widely into clinical practice.

La douleur ou la gêne thoracique sont des symptômes fréquents qui peuvent poser un dilemme diagnostique pour de nombreux médecins. Les erreurs de diagnostic d'une cause aiguë ou chronique progressive d'origine cardiaque peuvent d'ailleurs entraîner un risque considérable de morbidité et de mortalité. La présente synthèse porte sur les différentes options et modalités d'établissement du diagnostic et de la gravité d'une coronaropathie. Un algorithme efficace pour le choix des tests doit être adapté à chaque patient afin de maximiser l'exactitude diagnostique dans les plus brefs délais, de déterminer le pronostic à court et à long terme, et de permettre une mise en œuvre de traitements fondés sur des données probantes tout en tenant compte des coûts. Un algorithme décisionnel a donc été conjointement mis au point (www.chowmd.ca/cadtesting) et pourrait être largement adopté dans la pratique clinique.

An internal ribosome entry site in the coding region of tyrosyl-DNA phosphodiesterase 2 drives alternative translation start.

Tyrosyl-DNA phosphodiesterase 2 (TDP2) is a multifunctional protein that has been implicated in a myriad of cellular pathways. Although most well-known for its phosphodiesterase activity removing stalled topoisomerase 2 from DNA, TDP2 has also been shown to interact with both survival and apoptotic mitogen-activated protein kinase (MAPK) signaling cascades. Moreover, it facilitates enterovirus replication and has been genetically linked to neurological disorders ranging from Parkinson's disease to dyslexia. To accurately evaluate TDP2 as a therapeutic target, we need to understand how TDP2 performs such a wide diversity of functions. Here, we use cancer cell lines modified with CRISPR/Cas9 or stably-expressed TDP2-targeted shRNA and transfection of various TDP2 mutants to show that its expression is regulated at the translational level via an internal ribosome entry site (IRES) that initiates translation at codon 54, the second in-frame methionine of the TDP2 coding sequence. We observed that this IRES drives expression of a shorter, N-terminally truncated isoform of TDP2, ΔN-TDP2, which omits a nuclear localization sequence. Additionally, we noted that ΔN-TDP2 retains phosphodiesterase activity and is protective against etoposide-induced cell death, but co-immunoprecipitates with fewer high-molecular-weight ubiquitinated peptide species, suggesting partial loss-of-function of TDP2's ubiquitin-association domain. In summary, our findings suggest the existence of an IRES in the 5' coding sequence of TDP2 that translationally regulates expression of an N-terminally truncated, cytoplasmic isoform of TDP2. These results shed light on the regulation of this multifunctional protein and may inform the design of therapies targeting TDP2 and associated pathways.

How Are Ocular Signs and Symptoms of Dry Eye Associated With Depression in Women With and Without Sjögren Syndrome?

PURPOSE: To determine whether ocular phenotypic features of keratoconjunctivitis sicca (KCS) and/or participant-reported symptoms of dry eye disease are associated with depression in women participants enrolled in the Sjögren's International Collaborative Clinical Alliance (SICCA). DESIGN: Cross-sectional study. METHODS: Women enrolled in the SICCA registry from 9 international research sites. Participants met at least 1 of 5 inclusion criteria for registry enrollment (including complaints of dry eyes or dry mouth, a previous diagnosis of Sjögren syndrome (SS), abnormal serology (positive anti-Sjögren syndrome antigen A and/or B [anti-SSA and/or anti-SSB]), or elevated antinuclear antibody and rheumatoid factor), bilateral parotid gland enlargement, or multiple dental caries). At baseline, participants had oral, ocular, and rheumatologic examination; blood and saliva collection; and a labial salivary gland biopsy (LSGB). They also completed an interview and questionnaires including assessment of depression with the Patient Health Questionnaire 9 (PHQ-9). Univariate logistic regression was used to assess the association between depression and demographic characteristics, participant-reported health, phenotypic features of Sjögren syndrome, and participant-reported symptoms. Mixed-effects modeling was performed to determine if phenotypic features of KCS and/or participant-reported symptoms of dry eye disease were associated with depression, controlling for health, age, country or residence, and sex and allowing for nonindependence within geographic site. RESULTS: Dry eye complaints produced a 1.82-fold (95% confidence interval [CI] 1.38-2.40) higher odds of having depression compared to being symptom-free (P < .001). Additionally, complaints of specific ocular sensations were associated with a higher odds of depression including burning sensation (odds ratio 2.25, 95% CI 1.87-2.72, P < .001) compared to those without complaints. In both women with and without SS, the presence of symptoms of dry eyes and/or dry mouth rather than SS itself resulted in higher odds of depression. One particular ocular phenotypic feature of SS, a positive ocular staining score, was inversely correlated with depression. CONCLUSIONS: Participant-reported eye symptoms, particularly specific ocular sensations such as burning, were found to be positively associated with individual American College of Rheumatology/EUropean League Against Rheumatism (ACR/EULAR) SS criteria items.

Health-related quality of life and depression among participants in the Sjögren's International Collaborative Clinical Alliance registry.

OBJECTIVE: To examine health-related quality of life (HRQoL) and depression among participants in an international Sjögren's syndrome (SS) registry, comparing those with and without SS. METHODS: Cross-sectional study of participants in the Sjögren's International Collaborative Clinical Alliance (SICCA) registry. The 2016 American College of Rheumatology/European League Against Rheumatism SS classification criteria were used to determine disease status. HRQoL was assessed using the Short Form 12, version 2 Health Survey to derive scores for physical component summary (PCS) and mental component summary (MCS). Depression was assessed using the 9-Item Patient Health Questionnaire. Multivariate linear and logistic regression analyses were performed to identify predictors of HRQoL and depression while controlling for potential confounders. RESULTS: Among 2401 SICCA participants who had symptoms of dry eyes and dry mouth, 1051 had SS (44%) and 1350 did not (56%). After controlling for confounders, when compared with non-SS participants, those with SS had better PCS (p<0.001, ß=2.43, 95% CI 1.57 to 3.29), MCS (p=0.002, ß=1.37, 95% CI 0.50 to 2.23) and lower adjusted odds of depression (p<0.001, OR 0.67, 95% CI 0.55 to 0.81). Other significant predictors of HRQoL and depression included employment, country of residence and use of medication with anticholinergic effect or for management of SS-related signs and symptoms. CONCLUSION: Our results suggest that among symptomatic patients, having a diagnosis of SS may be associated with better emotional and psychological well-being compared with patients without a diagnosis. Having a definitive diagnosis of SS may encourage patients to obtain a better understanding of their disease and have coping mechanisms in place to better manage their symptoms.

European Society of Cardiology Guideline-Adherent Antithrombotic Treatment and Risk of Mortality in Asian Patients with Atrial Fibrillation.

This study compared the risk of mortality in atrial fibrillation (AF) patients treated adherent to the 2012 European Society of Cardiology (ESC) guidelines for stroke prevention and those who were not treated according to guideline recommendations. This study used the Taiwan National Health Insurance Research Database. From 1996 to 2011, 354,649 newly diagnosed AF patients were identified as the study population. Among the study cohort, 45,595 and 309,054 patients were defined as Guideline-Adherent and Non-Adherent groups, respectively. During the follow up of 1,480,280 person-years, 133,552 (37.7%) patients experienced mortality. The risk of mortality was lower among AF patients whose treatment was adherent to the guideline recommendation for stroke prevention than those whose treatment was not (annual risk of mortality = 4.3% versus 10.0%) with an adjusted hazard ratio of 0.62 (95% confidence interval = 0.61-0.64, p value < 0.001) after adjusting for age, gender, CHA2DS2-VASc score and antiplatelet therapy. The findings were consistently observed after propensity matching analysis. In conclusion, the risk of mortality was lower for AF patients who were treated according to the antithrombotic recommendations of the 2012 ESC guidelines, guided by the CHA2DS2-VASc score. Better efforts to implement guidelines would lead to improved outcomes for patients with AF.

Presence of diabetic microvascular complications does not incrementally increase risk of ischemic stroke in diabetic patients with atrial fibrillation: A nationwide cohort study.

Conventional stroke risk prediction tools used in atrial fibrillation (AF) incorporate the presence of diabetes mellitus (DM) as a risk factor. However, it is unknown whether this risk is homogenous or dependent on the presence of diabetic microvascular complications, such as diabetic retinopathy, nephropathy, and neuropathy. The present study examined the risk of ischemic stroke in diabetic patients with and without microvascular complications. The present study used the National Health Insurance Research Database in Taiwan with detailed healthcare data on all-comers to the Taiwanese medical system from January 1, 1996 to December 31, 2011. AF and DM were identified when listed as discharge diagnoses or confirmed more than twice in the outpatient department. Patients on antithrombotic agents were excluded. The clinical endpoint was ischemic stroke. Among the 50,180 AF patients with DM, the majority had no microvascular complications (72.7%), while 2.6% had diabetic retinopathy, 8.4% had diabetic nephropathy, and 16.1% had diabetic neuropathy. Ischemic stroke occurred in 6003 patients, with a 4.74% annual risk of ischemic stroke. When compared with DM patients without microvascular complications, those with diabetic retinopathy, nephropathy, or neuropathy had higher incidences of ischemic stroke (4.65 vs 5.07, 4.77, or 5.20 per 100 person-years, respectively). However, after adjusting for confounding factors, the differences were no longer significant. In a large nationwide AF cohort with DM, risk of ischemic stroke was similar between patients with and without microvascular complications, suggesting that risk stratification of these patients does not require inclusion of diabetic retinopathy, nephropathy, and neuropathy.

The First Dedicated Cardiac Rehabilitation Program for Patients With Spontaneous Coronary Artery Dissection: Description and Initial Results.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) is an important cause of myocardial infarction in women, but the role of rehabilitation after SCAD is unclear. METHODS: We designed a dedicated SCAD cardiac rehabilitation (SCAD-CR) program for our SCAD survivors at Vancouver General Hospital. This program encompasses a multidisciplinary approach including exercise rehabilitation, psychosocial counselling, dietary and cardiovascular disease education, and peer group support. Exercise and educational classes were scheduled weekly with a targeted participation of 6 months. Psychosocial counselling, mindful living sessions, social worker and psychiatry evaluations, and peer-group support were offered. RESULTS: We report our first consecutive cohort of 70 SCAD women who joined SCAD-CR from November 2011 to April 2015. The average age was 52.3 ± 8.4 years. Mean participation duration was 12.4 ± 10.5 weeks; 28 completed 6 months, 48 completed ≥ 1 month. At entry, 44 (62.9%) had recurrent chest pains and average metabolic equivalents on exercise treadmill test was 10.1 ± 3.3. At program exit, the proportion with recurrent chest pains was lower (37.1%) and average metabolic equivalents was higher 11.5 ± 3.5 (both P < 0.001). There was a significant improvement in the STOP-D depression questionnaire, with mean scores of 13.0 ± 1.4 before and 8.0 ± 1.7 after the SCAD-CR (P = 0.046). Twenty (28.6%) social worker referrals and 19 (27.1%) psychiatry referrals were made. Mean follow-up was 3.8 ± 2.9 years from the presenting SCAD event, and the major cardiac adverse event rate was 4.3%, lower than our non-SCAD-CR cohort (n = 145; 26.2%; P < 0.001). CONCLUSIONS: This is the first dedicated SCAD-CR program to address the unique exercise and psychosocial needs of SCAD survivors. Our program appears safe and beneficial in improving chest pain, exercise capacity, psychosocial well-being and cardiovascular events.

A Case of Kounis Type I in a Young Woman With Samter's Triad.

Kounis syndrome is defined as an acute coronary syndrome triggered by allergic or hypersensitivity reactions resulting in mast cell and platelet activation. Numerous causes have been described, including various drugs, medical conditions, and environmental exposures. Samter's triad consists of nasal polyps, asthma, and aspirin (or nonsteroidal anti-inflammatory drug) sensitivity. We describe a case of Kounis type I in a young woman with Samter's triad who presented with cardiac arrest on 3 occasions. Ergonovine provocation testing established the diagnosis of coronary vasospasm. The patient has derived significant benefit from calcium channel blockers.

Gingival pustules and sterile diffuse sclerosing osteomyelitis as a feature of synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome.

Synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome represents the rare co-occurrence of sterile inflammatory osteoarticular disease in association with a variety of cutaneous manifestations. Oral involvement is uncommon. The etiology of SAPHO is complex and is likely the combined result of infectious, genetic, and immunologic factors. Due to diverse clinical presentations, SAPHO is difficult to diagnose. Here, we describe the case of a 74-year-old man, who had a history of SAPHO syndrome and presented with gingival pustules and sterile diffuse sclerosing osteomyelitis of the mandible. This is the first case report describing neutrophilic mucositis as a feature of SAPHO.

A Comprehensive Analysis of Replicative Lifespan in 4,698 Single-Gene Deletion Strains Uncovers Conserved Mechanisms of Aging.

Many genes that affect replicative lifespan (RLS) in the budding yeast Saccharomyces cerevisiae also affect aging in other organisms such as C. elegans and M. musculus. We performed a systematic analysis of yeast RLS in a set of 4,698 viable single-gene deletion strains. Multiple functional gene clusters were identified, and full genome-to-genome comparison demonstrated a significant conservation in longevity pathways between yeast and C. elegans. Among the mechanisms of aging identified, deletion of tRNA exporter LOS1 robustly extended lifespan. Dietary restriction (DR) and inhibition of mechanistic Target of Rapamycin (mTOR) exclude Los1 from the nucleus in a Rad53-dependent manner. Moreover, lifespan extension from deletion of LOS1 is nonadditive with DR or mTOR inhibition, and results in Gcn4 transcription factor activation. Thus, the DNA damage response and mTOR converge on Los1-mediated nuclear tRNA export to regulate Gcn4 activity and aging.

Spontaneous Coronary Artery Dissection Misdiagnosed as Takotsubo Cardiomyopathy: A Case Series.

Spontaneous coronary artery dissection (SCAD) and Takotsubo cardiomyopathy (TTC) can both cause myocardial infarction with subsequent normalization of wall motion abnormality. Angiograms of patients with TTC at Vancouver General Hospital were reviewed for SCAD. Clinical and investigational characteristics were recorded. Nine women with nonatherosclerotic SCAD were misdiagnosed as having TTC. Their average age was 55 years. Five patients had hypertension and 4 had emotional or physical stress. Fibromuscular dysplasia was present in 4 women. Wall motion abnormalities corresponded to dissected artery location and subsequently resolved. SCAD should be included in the differential diagnosis of patients suspected of having TTC and coronary angiograms scrutinized for subtle SCAD.

Warfarin Monotherapy in Atrial Fibrillation Patients With Stable Coronary Disease One Year After Myocardial Infarction/Stent: Two Birds With One Stone?

Patients with atrial fibrillation and stable coronary artery disease remain a therapeutic challenge because of the different antithrombotic therapies for the 2 conditions and the increase in bleeding with concomitant antiplatelet and anticoagulant medications. Current guidelines extrapolated data from studies of antithrombotic regimens of each condition separately but there is limited evidence for the optimal regimen in patients with atrial fibrillation and stable coronary artery disease beyond the first year after an acute coronary syndrome or stent implantation. In this review we suggest that warfarin monotherapy is sufficient for this patient population beyond 1 year.

Therapeutic regulatory T cells subvert effector T cell function in inflamed islets to halt autoimmune diabetes.

Therapeutic regulatory T cells (Tregs) can reverse pre-established autoimmune pathology. In this study, using a mouse model of autoimmune diabetes, we aimed to determine the means by which therapeutic Tregs control islet inflammation. Islet Ag-specific Tregs infiltrated inflamed islets soon after infusion into prediabetic mice, which was quickly followed by a selective reduction of mRNA associated with effector T cells in the islets. This change was partially due to decreased CD8(+) T cell accumulation in the tissue. CD8(+) T cells that remained in the islets after Treg treatment were able to engage dendritic cells in a manner similar to that found in untreated mice, consistent with the retention of an activated phenotype by islet dendritic cells shortly after Treg treatment. Nonetheless, Treg treatment abrogated IFN-γ production by intraislet CD8(+) and CD4(+) T cells at the protein level with minimal effect on IFN-γ mRNA. Sustained expression of IFN-γ protein by effector T cells was dependent on common γ-chain cytokine activation of the mTOR pathway, which was suppressed in islet CD8(+) T cells in vivo after Treg treatment. These multifaceted mechanisms underlie the efficacy of therapeutic Treg subversion of effector T cell functions at the site of inflammation to restore normal tissue homeostasis.

Basis for sex-specific expression of Takotsubo cardiomyopathy, cardiac syndrome X, and spontaneous coronary artery dissection.

Takotsubo cardiomyopathy, cardiac syndrome X, and spontaneous coronary artery dissection are cardiovascular syndromes with a predilection for women. A complex interplay between neurohormonal factors, genetic influences, anatomic alterations, and other factors together affect cardiovascular function. Specifically, a high, variable, or deficient estrogen state leads to vasomotor instability with propensity toward vasoconstriction and endothelial dysfunction that predispose women to myocardial impairment, microvascular dysfunction, and coronary arterial wall instability. As the predominant sex hormone in women, fluctuating estrogen levels lead to a sex disparity in the expression of these cardiac entities. This review explores the research on sex-based differences of the neurohormonal, genetic, and mechanical factors in the normal cardiovascular system and in the pathophysiology of these 3 conditions. The understanding of their prevalence, pathogenesis, and sex disparity allows improved recognition, management, and support of female patients inflicted with these syndromes.

End-of-life cell cycle arrest contributes to stochasticity of yeast replicative aging.

There is growing evidence that stochastic events play an important role in determining individual longevity. Studies in model organisms have demonstrated that genetically identical populations maintained under apparently equivalent environmental conditions display individual variation in life span that can be modeled by the Gompertz-Makeham law of mortality. Here, we report that within genetically identical haploid and diploid wild-type populations, shorter-lived cells tend to arrest in a budded state, while cells that arrest in an unbudded state are significantly longer-lived. This relationship is particularly notable in diploid BY4743 cells, where mother cells that arrest in a budded state have a shorter mean life span (25.6 vs. 35.6) and larger coefficient of variance with respect to individual life span (0.42 vs. 0.32) than cells that arrest in an unbudded state. Mutations that cause genomic instability tend to shorten life span and increase the proportion of the population that arrest in a budded state. These observations suggest that randomly occurring damage may contribute to stochasticity during replicative aging by causing a subset of the population to terminally arrest prematurely in the S or G2 phase of the cell cycle.

Real-time transmission to real-time patient care: a tale of 4 devices.

We report a case in which a patient with dilated cardiomyopathy presented with syncope, terminated by a shock from his implantable cardioverter defibrillator. However, subsequent interrogation of the device revealed no tachycardia detection or treatment parameters. The mystifying details of the case were unravelled by remote consultation with the staff electrophysiologist and the use of smart phone-transmitted live images. This case highlights the use of mobile phone-facilitated video conferencing in urgent management of intracardiac device therapy. Judicious use of this technology has the potential to deliver effective and cost-effective solutions for many device-related emergencies in patients at remote settings.

Dietary restriction and mitochondrial function link replicative and chronological aging in Saccharomyces cerevisiae.

Chronological aging of budding yeast cells results in a reduction in subsequent replicative life span through unknown mechanisms. Here we show that dietary restriction during chronological aging delays the reduction in subsequent replicative life span up to at least 23days of chronological age. We further show that among the viable portion of the control population aged 26days, individual cells with the lowest mitochondrial membrane potential have the longest subsequent replicative lifespan. These observations demonstrate that dietary restriction modulates a common molecular mechanism linking chronological and replicative aging in yeast and indicate a critical role for mitochondrial function in this process.

Stress profiling of longevity mutants identifies Afg3 as a mitochondrial determinant of cytoplasmic mRNA translation and aging.

Although environmental stress likely plays a significant role in promoting aging, the relationship remains poorly understood. To characterize this interaction in a more comprehensive manner, we examined the stress response profiles for 46 long-lived yeast mutant strains across four different stress conditions (oxidative, ER, DNA damage, and thermal), grouping genes based on their associated stress response profiles. Unexpectedly, cells lacking the mitochondrial AAA protease gene AFG3 clustered strongly with long-lived strains lacking cytosolic ribosomal proteins of the large subunit. Similar to these ribosomal protein mutants, afg3Δ cells show reduced cytoplasmic mRNA translation, enhanced resistance to tunicamycin that is independent of the ER unfolded protein response, and Sir2-independent but Gcn4-dependent lifespan extension. These data demonstrate an unexpected link between a mitochondrial protease, cytoplasmic mRNA translation, and aging.

The role of aspirin in post-polypectomy bleeding--a retrospective survey.

BACKGROUND: Bleeding following colonoscopic polypectomy is a common complication and has been reported to occur in up to 6.1% of patients. Several risk factors have been discussed but their overall contribution to post-polypectomy bleeding remains controversial. The aim of the study was to determine the rate of post polypectomy bleeding and to analyse the role of potential risk factors especially the role of aspirin. METHODS: We conducted a retrospective cohort study of all patients who underwent polypectomy at Dunedin Hospital, New Zealand between January 2007 and June 2009. RESULTS: During the study period, 514 patients underwent colonoscopy with polypectomy and a total of 1502 polyps were removed. From further analysis we excluded 21 patients; 15 patients had surgery immediately after colonoscopy for the diagnosis of colorectal carcinoma and 6 patients presented with symptoms of an acute lower gastrointestinal bleed prior to colonoscopy. Of the remaining 493 patients, 11 patients (2.2%) presented with post-polypectomy bleeding within 30 days of the investigation of which 8 were on aspirin. In total 145 patients were taking aspirin prior to colonoscopy and 348 patients were not taking aspirin. The use of aspirin was associated with an increased prevalence of post-polypectomy bleeding (OR=6.72, 95% C.I. 1.76 to 25.7). Interestingly, the use of non-steroidal anti-inflammatory drugs (NSAIDs) was not associated with risk of bleeding after polypectomy (OR=2.82, 95% C.I, 0.34 to 23.3). CONCLUSION: Our study confirmed a significantly increased risk of lower gastrointestinal bleeding following polypectomy in patients taking aspirin. We would recommend approaching the patient on aspirin coming forward for a colonoscopy with potential polypectomy with caution.