Is Upper Extremity or Lower Extremity Function More Important for Patient Satisfaction? An Analysis of 24-Month Outcomes from the QOD Cervical Spondylotic Myelopathy Cohort.

STUDY DESIGN: Retrospective analysis of a prospective, multicenter registry. OBJECTIVE: To assess whether upper or lower limb mJOA improvement more strongly associates with patient satisfaction after surgery for cervical spondylotic myelopathy (CSM). SUMMARY OF BACKGROUND DATA: The modified Japanese Orthopaedic Association (mJOA) is commonly used to assess functional status in patients with CSM. Patients present with upper and/or lower extremity dysfunction, and it is unclear whether improvement in one and/or both symptoms drives postoperative patient satisfaction. METHODS: This study utilizes the prospective Quality Outcomes Database (QOD) CSM data set. Clinical outcomes included mJOA and North American Spine Society (NASS) satisfaction. The upper limb mJOA score was defined as upper motor plus sensory mJOA, and the lower limb mJOA as lower motor plus sensory mJOA. Ordered logistic regression was used to determine whether upper or lower limb mJOA was more closely associated with NASS satisfaction, adjusting for other covariates. RESULTS: Overall, 1141 patients were enrolled in the QOD CSM cohort. In all, 780 had both preoperative and 24-month mJOA scores, met inclusion criteria, and were included for analysis. The baseline mJOA was 12.1±2.7, and postoperatively, 85.6% would undergo surgery again (NASS 1 or 2, satisfied). Patients exhibited mean improvement in both upper (baseline:3.9±1.4 vs. 24 mo:5.0±1.1, P<0.001) and lower limb mJOA (baseline:3.9±1.4 vs. 24 mon:4.5±1.5, P<0.001); however, the 24-month change in the upper limb mJOA was greater (upper:1.1±1.6 vs. lower:0.6±1.6, P<0.001). Across 24-month NASS satisfaction, the baseline upper and lower limb mJOA scores were similar (pupper=0.28, plower=0.092). However, as satisfaction decreased, the 24-month change in upper and lower limb mJOA decreased as well (pupper<0.001, plower<0.001). Patients with NASS scores of 4 (lowest satisfaction) did not demonstrate significant differences from baseline in upper or lower limb mJOA (P>0.05). In ordered logistic regression, NASS satisfaction was independently associated with upper limb mJOA improvement (OR=0.81; 95% CI: 0.68-0.97; P=0.019) but not lower limb mJOA improvement (OR=0.84; 95% CI: 0.70-1.0; P=0.054). CONCLUSIONS: As the magnitude of upper and lower mJOA improvement decreased postoperatively, so too did patient satisfaction with surgical intervention. Upper limb mJOA improvement was a significant independent predictor of patient satisfaction, whereas lower limb mJOA improvement was not. These findings may aid preoperative counseling, stratified by patients' upper and lower extremity treatment expectations. LEVEL OF EVIDENCE: Level-III.

Prevalence of Subclinical Atrial Fibrillation in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Atrial fibrillation (AF) is common in patients with heart failure with preserved ejection fraction (HFpEF) and is associated with poorer clinical outcomes. The prevalence of subclinical AF in patients with HFpEF remains unknown. OBJECTIVES: The aim of this study was to determine whether subclinical AF was more prevalent in individuals with HFpEF than in individuals without histories of heart failure (HF). METHODS: Patients with HFpEF with no prior diagnoses of AF were screened for subclinical AF, and the prevalence of subclinical AF was compared with that among control subjects without HF drawn from MESA (Multi-Ethnic Study of Atherosclerosis) who underwent the same electrocardiographic monitoring. Multivariable logistic regression was used to adjust for demographic and clinical comorbidities. RESULTS: Ninety patients with HFpEF and 1,230 MESA participants were included. Patients with HFpEF were younger (median age 69 years [Q1-Q3: 63-76 years] vs 72 years [Q1-Q3: 66-80 years]; P = 0.02), more obese (median body mass index 36 kg/m2 [Q1-Q3: 30-45 kg/m2] vs 27 kg/m2 [Q1-Q3: 24-30 kg/m2]; P < 0.001), and more likely to have diabetes (34% vs 21%; P = 0.01). The prevalence of subclinical AF was 8.9% in patients with HFpEF and 4.1% in non-HF participants. After multivariable adjustment for age, sex, race, body mass index, diabetes, smoking, and total analyzable time on electrocardiographic monitor, there was a significantly higher odds of subclinical AF in patients with HFpEF compared with MESA (OR: 3.01; 95% CI: 1.13-7.99; P = 0.03). CONCLUSIONS: Patients with HFpEF had a higher prevalence of subclinical AF than participants without HF from a community-based study. Screening for atrial arrhythmias may be appropriate among patients with HFpEF for timely initiation of thromboembolic prophylaxis and may identify individuals at greater risk for clinical decompensation.

Cervical laminoplasty versus laminectomy and posterior cervical fusion for cervical myelopathy: propensity-matched analysis of 24-month outcomes from the Quality Outcomes Database.

OBJECTIVE: Compared with laminectomy with posterior cervical fusion (PCF), cervical laminoplasty (CL) may result in different outcomes for those operated on for cervical spondylotic myelopathy (CSM). The aim of this study was to compare 24-month patient-reported outcomes (PROs) for laminoplasty versus PCF by using the Quality Outcomes Database (QOD) CSM data set. METHODS: This was a retrospective study using an augmented data set from the prospectively collected QOD Registry Cervical Module. Patients undergoing laminoplasty or PCF for CSM were included. Using the nearest-neighbor method, the authors performed 1:1 propensity matching based on age, operated levels, and baseline modified Japanese Orthopaedic Association (mJOA) and visual analog scale (VAS) neck pain scores. The 24-month PROs, i.e., mJOA, Neck Disability Index (NDI), VAS neck pain, VAS arm pain, EQ-5D, EQ-VAS, and North American Spine Society (NASS) satisfaction scores, were compared. Only cases in the subaxial cervical region were included; those that crossed the cervicothoracic junction were excluded. RESULTS: From the 1141 patients included in the QOD CSM data set who underwent anterior or posterior surgery for cervical myelopathy, 946 (82.9%) had 24 months of follow-up. Of these, 43 patients who underwent laminoplasty and 191 who underwent PCF met the inclusion criteria. After matching, the groups were similar for baseline characteristics, including operative levels (CL group: 4.0 ± 0.9 vs PCF group: 4.2 ± 1.1, p = 0.337) and baseline PROs (p > 0.05), except for a higher percentage involved in activities outside the home in the CL group (95.3% vs 81.4%, p = 0.044). The 24-month follow-up for the matched cohorts was similar (CL group: 88.4% vs PCF group: 83.7%, p = 0.534). Patients undergoing laminoplasty had significantly lower estimated blood loss (99.3 ± 91.7 mL vs 186.7 ± 142.7 mL, p = 0.003), decreased length of stay (3.0 ± 1.6 days vs 4.5 ± 3.3 days, p = 0.012), and a higher rate of routine discharge (88.4% vs 62.8%, p = 0.006). The CL cohort also demonstrated a higher rate of return to activities (47.2% vs 21.2%, p = 0.023) after 3 months. Laminoplasty was associated with a larger improvement in 24-month NDI score (-19.6 ± 18.9 vs -9.1 ± 21.9, p = 0.031). Otherwise, there were no 3- or 24-month differences in mJOA, mean NDI, VAS neck pain, VAS arm pain, EQ-5D, EQ-VAS, and distribution of NASS satisfaction scores (p > 0.05) between the cohorts. CONCLUSIONS: Compared with PCF, laminoplasty was associated with decreased blood loss, decreased length of hospitalization, and higher rates of home discharge. At 3 months, laminoplasty was associated with a higher rate of return to baseline activities. At 24 months, laminoplasty was associated with greater improvements in neck disability. Otherwise, laminoplasty and PCF shared similar outcomes for functional status, pain, quality of life, and satisfaction. Laminoplasty and PCF achieved similar neck pain scores, suggesting that moderate preoperative neck pain may not necessarily be a contraindication for laminoplasty.

Palliative care in a rural surgery residency program: an educational needs assessment.

BACKGROUND: There is a deficiency of palliative care education in surgical residency programs and a lack of research on palliative care education in rural surgery residency programs. Because rural palliative care presents unique challenges due to fewer specialists and resources, we investigated potential areas of improvement in palliative care education in a rural general surgery residency program. METHODS: An anonymous survey was sent to all residents of a rural general surgery residency program. The survey assessed prior hospice/palliative care education in medical school, prior volunteering experience in palliative care, comfort with having "goals of care" discussions and delivering serious news, and perceived indications for palliative care consultation. A follow-up survey assessed attitudes and interest related to palliative care education integration in a rural surgical residency program. RESULTS: Of 17 residents, 14 (82.4%) responded to the initial survey. Four respondents (28.6%) had over a half day of palliative care education in medical school. Eight of fourteen respondents (57.1%) feel comfortable having "goals of care" discussions: 0/4 interns (0%) compared to 8/10 junior and senior residents (80%). Half of respondents feel comfortable delivering serious news: 1/4 interns (25%) compared to 6/10 junior and senior residents (60%). All respondents agreed that palliative care education is necessary. Four themes were identified in content analysis of perceived indications for palliative care consultation: future planning, deferring to the expert, patient/family education, and surgeon/trainee discomfort. The follow-up survey revealed perceived limitations in palliative care resources available in a rural surgery setting. CONCLUSIONS: These results highlight the need for formal palliative care education in a rural surgery residency program. Throughout training, residents appear to develop more comfort with "goals of care" discussions than delivering serious news. In response, we are instituting palliative care discussions during educational conference, including interactive simulations to improve communication skills, and a palliative care telemedicine elective.

Rate Versus Rhythm Control in Heart Failure Patients with Post-Operative Atrial Fibrillation After Cardiac Surgery.

BACKGROUND: Whether rhythm control for post-operative atrial fibrillation after cardiac surgery (POAF) is superior to rate control in patients with heart failure or systolic dysfunction (HF) is not known. METHODS: We performed a post-hoc analysis of a trial by the Cardiothoracic Surgical Trials Network, which randomized patients with POAF after cardiac surgery to rate control or rhythm control with amiodarone/cardioversion. We assessed subgroups of trial participants defined by heart failure/cardiomyopathy history or left ventricular ejection fraction (LVEF) < 50%. We conducted a stratified analysis in patients with and without HF to explore outcomes of rhythm versus rate control strategy. RESULTS: Of 523 subjects with POAF after cardiac surgery, 131 (25%) had HF. 49% of HF patients were randomized to rhythm control. In HF patients, rhythm control was associated with less atrial fibrillation within the first 7 days. There were no differences in rhythm at 30- and 60-day follow-up. In the HF group, there were significantly more subjects with AF < 48 hours in the rhythm control group compared to rate control group- 68.8% compared to 46.3%, P=0.009. By comparison, in the non-HF stratum, 54.4% of the rate control group had AF < 48 hours compared to 63.5% of the rhythm control group (P=0.067).), though there was no significant interaction of heart failure with cardiac rhythm at 7 days (Pinteraction 0.16). CONCLUSION: Rhythm control for HF patients with POAF after cardiac surgery increases early restoration of sinus rhythm. Rate and rhythm control are both reasonable for HF patients with AF after cardiac surgery.

The role of timing in treatment of atrial fibrillation: An AFFIRM substudy.

BACKGROUND: In contrast to historical trials, the Early Treatment of Atrial Fibrillation for Stroke Prevention Trial (EAST-AFNET 4) suggests the superiority of early rhythm control over rate control in patients with recent-onset atrial fibrillation (AF). The relative contribution of timing vs improvement in AF therapeutics over time is unclear. OBJECTIVE: This study aimed to isolate the assessment of early intervention for AF from temporal changes in AF treatments through a secondary analysis of subjects from the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. METHODS: We compared rate and rhythm control treatments in AFFIRM subjects stratified by time from their diagnosis of AF. Time-to-event analysis was performed to compare all-cause mortality, cardiovascular hospitalizations, stroke, and number of hospitalization days. RESULTS: Of the 4060 AFFIRM subjects, 2526 subjects (62.2%) had their first episode of AF within 6 months of study enrollment. Participants with "new" AF had a decreased risk of all-cause mortality (P = .001) than did those with prior AF diagnoses. Individuals previously diagnosed with AF were similar in age and demographic characteristics, but had more medical comorbidities, including myocardial infarction (P = .006), diabetes mellitus (P = .002), smoking (P = .003), and hepatic or renal comorbidities (P = .008). There were no differences in mortality, cardiovascular hospitalizations, or stroke between rate and rhythm control strategies in either AF subgroup. CONCLUSION: AFFIRM subjects diagnosed with AF within 6 months of study enrollment showed no difference in survival, cardiovascular hospitalization, or ischemic stroke between rate and rhythm control strategies. Superiority of rhythm control strategies reported by newer AF trials may be more attributable to the refinement of AF therapies and less related to the timing of intervention.

Three-Dimensional Volumetric Assessment of Diastolic Function by Cardiac Magnetic Resonance Imaging: The Multi-Ethnic Study of Atherosclerosis (MESA) / Avaliação Volumétrica Tridimensional da Função Diastólica Por Ressonância Magnética Cardíaca: Multi-Ethnic Study Of Atherosclerosis (MESA)

Abstract Background: Cardiac Magnetic Resonance is in need of a simple and robust method for diastolic function assessment that can be done with routine protocol sequences. Objective: To develop and validate a three-dimensional (3D) model-based volumetric assessment of diastolic function using cardiac magnetic resonance (CMR) imaging and compare the results obtained with the model with those obtained by echocardiography. Methods: The study participants provided written informed consent and were included if having undergone both echocardiography and cine steady-state free precession (SSFP) CMR on the same day. Guide points at the septal and lateral mitral annulus were used to define the early longitudinal relaxation rate (E'), while a time-volume curve from the 3D model was used to assess diastolic filling parameters. We determined the correlation between 3D CMR and echocardiography and the accuracy of CMR in classifying the diastolic function grade. Results: The study included 102 subjects. The E/A ratio by CMR was positively associated with the E/A ratio by echocardiography (r = 0.71, p < 0.0001). The early diastolic relaxation velocity by tissue Doppler and longitudinal relaxation rate for the lateral mitral annulus displacement were positively associated (p = 0.007), as were the ratio between Doppler E/e' and CMR E/E' (p = 0.01). CMR-determined normalized peak E (NE) and deceleration time (DT) were able to predict diastolic dysfunction (areas under the curve [AUCs] = 0.70 and 0.72, respectively). In addition, the lateral E/E' ratio showed good utility in identifying diastolic dysfunction (AUC = 0.80). Overall, echocardiography and CMR interobserver and intraobserver agreements were excellent (intraclass correlation coefficient range 0.72 - 0.97). Conclusion: 3D modeling of standard cine CMR images was able to identify study subjects with reduced diastolic function and showed good reproducibility, suggesting a potential for a routine diastolic function assessment by CMR.

Resumo Fundamento: A ressonância magnética cardíaca necessita de um método simples e robusto para a avaliação da função diastólica que pode ser feito com sequências protocolares de rotina. Objetivo: Desenvolver e validar a avaliação volumétrica da função diastólica através de um modelo tridimensional (3D) com utilização de imagens de ressonância magnética cardíaca (RMC) e comparar os resultados obtidos com este modelo com os obtidos por ecocardiografia. Métodos: Os participantes do estudo assinaram um termo de consentimento e foram incluídos se tivessem sido submetidos no mesmo dia tanto à ecocardiografia quanto à cine RMC com precessão livre no estado estacionário (steady-state free precession, SSFP). Pontos-guia foram utilizados no anel mitral septal e lateral para definir a velocidade de estiramento no início da diástole (E'), enquanto curvas de volume-tempo do modelo 3D foram utilizadas para avaliar os parâmetros de enchimento diastólico. Foram determinadas a correlação entre a RMC 3D e a ecocardiografia, além da acurácia da RMC em classificar o grau de função diastólica. Resultados: Ao todo, 102 sujeitos foram incluídos no estudo. A razão E/A pela RMC esteve positivamente associada com a razão E/A obtida pela ecocardiografia (r = 0,71, p < 0,0001). Estiveram positivamente associadas a velocidade de relaxamento diastólico inicial ao Doppler tecidual e a velocidade de relaxamento longitudinal de deslocamento do anel mitral lateral (p = 0,007), bem como a razão entre E/e' por Doppler e E/E' pela RMC (p = 0,01). A velocidade normalizada de pico de enchimento (EM) determinada pela RMC e o tempo de desaceleração (TD) foram capazes de predizer a disfunção diastólica (áreas sob a curva [AUCs] = 0,70 e 0,72, respectivamente). Além disso, a razão E/E' lateral mostrou boa utilidade para a identificação da disfunção diastólica (AUC = 0,80). No geral, a ecocardiografia e a RMC apresentaram excelente concordância interobservador e intraobservador (coeficiente de correlação intraclasse 0,72 - 0,97). Conclusão: Uma modelagem 3D de imagens padrões de cine RMC foi capaz de identificar os indivíduos do estudo com função diastólica reduzida e mostrou uma boa reprodutibilidade, sugerindo ter potencial na avaliação rotineira da função diastólica por RMC.

Determinants of Potentially Inappropriate Medication Use among Community-Dwelling Older Adults.

OBJECTIVE: To examine the determinants of potentially inappropriate medication (PIM) use. DATA SOURCES/STUDY SETTING: U.S. nationally representative data on (n = 16,588) noninstitutionalized older adults (age ≥65) with drug use from the 2006-2010 Medical Expenditure Panel Survey. STUDY DESIGN: We operationalized the 2012 Beers Criteria to identify PIM use during the year, and we examined associations with individual-level characteristics hypothesized to be quality enabling or related to need complexity. PRINCIPAL FINDINGS: Almost one-third (30.9 percent) of older adults used a PIM. Multivariate results suggest that poor health status and high-PIM-risk conditions were associated with increased PIM use, while increasing age and educational attainment were associated with lower PIM use. Contrary to expectations, lack of a usual care source of care or supplemental insurance was associated with lower PIM use. Medication intensity appears to be in the pathway between both quality-enabling and need-complexity characteristics and PIM use. CONCLUSION: Our results suggest that physicians attempt to avoid PIM use in the oldest old but have inadequate focus on the high-PIM-risk conditions. Educational programs targeted to physician practice regarding high-PIM-risk conditions and patient literacy regarding medication use are potential responses.

CEACAM2 negatively regulates hemi (ITAM-bearing) GPVI and CLEC-2 pathways and thrombus growth in vitro and in vivo.

Carcinoembryonic antigen-related cell adhesion molecule-2 (CEACAM2) is a cell-surface glycoprotein expressed on blood, epithelial, and vascular cells. CEACAM2 possesses adhesive and signaling properties mediated by immunoreceptor tyrosine-based inhibitory motifs. In this study, we demonstrate that CEACAM2 is expressed on the surface and in intracellular pools of platelets. Functional studies of platelets from Ceacam2(-/-)-deficient mice (Cc2(-/-)) revealed that CEACAM2 serves to negatively regulate collagen glycoprotein VI (platelet) (GPVI)-FcRγ-chain and the C-type lectinlike receptor 2 (CLEC-2) signaling. Cc2(-/-) platelets displayed enhanced GPVI and CLEC-2-selective ligands, collagen-related peptide (CRP), collagen, and rhodocytin (Rhod)-mediated platelet aggregation. They also exhibited increased adhesion on type I collagen, and hyperresponsive CRP and CLEC-2-induced α and dense granule release compared with wild-type platelets. Furthermore, using intravital microscopy to ferric chloride (FeCl3)-injured mesenteric arterioles and laser-induced injury of cremaster muscle arterioles, we herein show that thrombi formed in Cc2(-/-) mice were larger and more stable than wild-type controls in vivo. Thus, CEACAM2 is a novel platelet immunoreceptor that acts as a negative regulator of platelet GPVI-collagen interactions and of ITAM receptor CLEC-2 pathways.

Comparison of two syngeneic orthotopic murine models of pancreatic adenocarcinoma.

BACKGROUND: Pancreatic adenocarcinoma has an extremely poor prognosis. The use of appropriate in vivo models is essential in devising methods to improve treatment outcomes. METHODS: A pancreatic adenocarcinoma model based on tumor injection into the pancreatic head was compared with a pancreatic tail injection model in C57/BL6 mice. The murine pancreatic adenocarcinoma cell line PAN02, dispersed in Matrigel™, was used for tumor induction. RESULTS: Tumors developed in all animals in both models. Tumor size was more consistent within the pancreatic tail group at 20 days following induction, with no evidence of metastatic disease. Animals in the pancreatic head injection group showed signs of reduced health by 20 days following injection and developed jaundice. Microscopic liver metastases were noted in some of these animals at this time point. The overall survival of animals at 40 days following tumor induction was significantly lower in the pancreatic head injection group (0% vs. 35%; p < .001). Multiple liver metastases were noted in five of 10 (50%) animals in the head injection group, without evidence of peritoneal metastases. In the pancreatic tail injection group, 18 of 20 (90%) animals had multiple peritoneal metastases, and nine of 20 (45%) animals had evidence of isolated liver deposits. Tumors in both regions of the pancreas had similar histologic characteristics, with a dense fibrotic stroma at the interface between the tumor and the normal pancreas. CONCLUSION: Pancreatic head and tail orthotopic cancer models produce consistent tumors, but the patterns of tumor spread and survival differ according to the site of injection.

ACE Project--advocating for clinical excellence: creating change in the delivery of palliative care.

BACKGROUND: Psychologists, social workers, and spiritual care professionals report inadequate preparation to maximize their effectiveness in advocating for institutional reform to meet oncology patients' diverse bio-psychosocial-spiritual and cultural needs. This article provides an overview of the ACE Project, a National Cancer Institute, 5 year, R25-funded transdisciplinary palliative care education program designed to enhance the advocacy and leadership skills of 301 competitively selected psycho-oncology professionals. METHODS: ACE Project participants identified an institutional goal, refined their goals during the course and received mentorship and support throughout the subsequent year. Participants were invited to return to a Reunion Conference in year five to report on their activities, network, and share the results of their change efforts. A subset of 28 ACE Project participants contributed to this OMEGA special issue. RESULTS: Participants' goals primarily focused on strategies to improve clinical care through program development and improvements in palliative care education within their institutions. CONCLUSIONS: The results of this transdisciplinary leadership skills-building program for psycho-oncology professionals affirm the feasibility and perceived need for the program. See the ACE Project website (http://www.cityofhope.org/education/health-professional-education/nursing-education/ACE-project/Pages/default.aspx) for additional program information.

Palliative care opportunities for women with advanced ovarian cancer associated with intraperitoneal chemotherapy.

Intraperitoneal chemotherapy poses both potential benefits as a cancer treatment and negative consequences on patient and family quality of life. The profound multi-dimensional quality of life impact of intraperitoneal (IP) chemotherapy upon women with advanced ovarian cancer makes the early integration of palliative care particularly important for this population. Numerous opportunities occur throughout the treatment process to improve the delivery of biopsychosocial-spiritual support to women receiving IP chemotherapy.

Toxicities, complications, and clinical encounters during intraperitoneal chemotherapy in 17 women with ovarian cancer.

PURPOSE OF THE RESEARCH: Intraperitoneal (IP) chemotherapy is a viable and superior treatment to standard intravenous (IV) chemotherapy in women with small volume residual ovarian cancer following optimal debulking. Despite this clinical advantage, widespread adoption of the treatment regimen has been hampered by concerns related to toxicities and complications. The purpose of this descriptive study was to describe nursing implications related to toxicities, complications and clinical encounters in 17 women with ovarian cancer who received IP chemotherapy. METHODS AND SAMPLE: Women with ovarian cancer who received IP chemotherapy at one NCI-designated comprehensive cancer center were accrued. Data related to IP chemotherapy summary, clinical encounters and admissions were obtained through comprehensive chart audits. KEY RESULTS: Common treatment-related toxicities included nausea and vomiting, fatigue, hypomagnesia, pain, neuropathy, anemia, and constipation. Reasons for dose-modifications were multi-factorial, and were primarily related to catheter complications and chemotherapy toxicities. The number of clinical encounters was high, and they were primarily related to admissions for inpatient IP chemotherapy and follow-up clinic visits. CONCLUSIONS: Treatment-related toxicities and complications were common in women with ovarian cancer who received IP chemotherapy. Use of IP chemotherapy results in multiple clinical encounters, such as outpatient clinic visits and inpatient admissions. Nursing is a critical part of the interdisciplinary approach in caring for women treated with IP chemotherapy. Interdisciplinary teams with high levels of knowledge and skills related to IP chemotherapy administration are needed to manage treatment-related toxicities and complications, and support multiple clinical encounters during treatment.

Understanding the genetics of coronary artery disease through the lens of noninvasive imaging.

Coronary artery disease is a common condition with a known heritable component that has spurred interest in genetic research for decades, resulting in a handful of candidate genes and an appreciation for the complexity of its genetic contributions. Recent advances in sequencing technologies have resulted in large-scale association studies, possibly adding to our current understanding of the genetics of coronary artery disease. Sifting through the statistical noise, however, requires the selection of effective phenotypic markers. New imaging technologies have improved our ability to detect subclinical atherosclerosis in a safe and reproducible manner in large numbers of patients. In this article, we propose that advances in imaging technology have generated improved phenotypic markers for genetic association studies of coronary artery disease.

MUC1 cytoplasmic tail: a potential therapeutic target for ovarian carcinoma.

Ovarian cancer is often a lethal disease, since the occult progression of the tumor within the peritoneal cavity results in late diagnosis and treatment failure. The identification of molecular events specific to metastasis is critical for the development of effective therapies. MUC1 is aberrantly overexpressed by most ovarian cancer and regarded as a molecular target for ovarian cancer. This review focuses on the latest advances regarding a signaling region in the MUC1 C-terminal subunit-mediated c-Src signaling pathways in malignant transformation, invasion and metastasis. Disruption of MUC1-C-terminal subunit-associated c-Src signaling by targeting the specific sites might represent a novel immunotherapeutic approach for the treatment of ovarian cancer.

Urotensin II promotes hypertrophy of cardiac myocytes via mitogen-activated protein kinases.

Urotensin II and its receptor are coexpressed in the heart and up-regulated during cardiac dysfunction. In cultured neonatal cardiomyocytes, we mimicked this up-regulation using an adenovirus to increase expression of the urotensin receptor. In this model system, urotensin II promoted strong hypertrophic growth and phenotypic changes, including cell enlargement and sarcomere reorganization. Urotensin II potently activated the MAPKs, ERK1/2 and p38, and blocking these kinases with PD098059 and SB230580, respectively, significantly inhibited urotensin II-mediated hypertrophy. In contrast, urotensin II did not activate JNK. The activation of ERK1/2 and p38 as well as cellular hypertrophy was independent of protein kinase C, and calcium and phosphoinositide 3-kinase, yet dependent on the capacity of the urotensin receptor to trans-activate the epidermal growth factor receptor. Urotensin II promoted the tyrosine phosphorylation of epidermal growth factor receptors, which was inhibited by the selective epidermal growth factor receptor kinase inhibitor, AG1478. These data indicate that perturbations in cardiac homeostasis, which lead to up-regulation of urotensin II receptors, promote urotensin II-mediated cardiomyocyte hypertrophy via ERK1/2 and p38 signaling pathways in an epidermal growth factor receptor-dependent manner.

Novel inhibitors of urokinase-type plasminogen activator and matrix metalloproteinase expression in metastatic cancer cell lines.

The plasminogen-activating (PA) and matrix metalloproteinase (MMP) enzyme systems are implicated in proteolytic turnover of the extracellular matrix (ECM) associated with biologic processes including wound healing, inflammation and angiogenesis. Aberrant expression of components of the PA and MMP enzyme systems occurs in the pathogenesis of metastatic cancer. Oxamflatin (Ox), a novel hydroxamic acid derivative, inhibits u-PA mRNA expression and proteolytic activity while simultaneously upregulating the expression of the natural inhibitor of u-PA, plasminogen activator inhibitor type 2 (PAI-2) in metastatic cancer cells. We have characterized the effects of Ox and a novel derivative, Metacept-1 (MCT-1), on PA and MMP-mediated proteolysis and invasion in several metastatic tumor lines. Both compounds are able to inhibit u-PA-, MMP-2- and MMP-9-mediated gene expression at low micromolar concentrations as well as u-PA- and MMP-mediated proteolysis as assessed by zymography, with MCT-1 being the more effective of the 2 agents in some assays. Cellular invasion assays correlate with gene expression and zymography experiments identifying both Ox and MCT-1 as able to inhibit invasion of metastatic cancer cell lines through matrigel at nanomolar concentrations, with MCT-1 more effective than Ox in 2 of the 3 cancer cell lines assessed.