Cyclin D1 targets hexokinase 2 to control aerobic glycolysis in myeloma cells.

Cancer cells are characterized by the Warburg effect, a shift from mitochondrial respiration to oxidative glycolysis. We report here the crucial role of cyclin D1 in promoting this effect in a cyclin-dependent kinase (CDK)4/6-independent manner in multiple myeloma (MM) cells. We show that the cyclin D1 oncoprotein targets hexokinase 2 (HK2), a major glycolysis regulator, through two original molecular mechanisms in the cytoplasmic and nuclear compartments. In the cytoplasm, cyclin D1 binds HK2 at the outer mitochondrial membrane, and in the nucleus, it binds hypoxia-inducible factor-1α (HIF1α), which regulates HK2 gene transcription. We also show that high levels of HK2 expression are correlated with shorter event-free survival (EFS) and overall survival (OS) in MM patients. HK2 may therefore be considered as a possible target for antimyeloma therapy.

The quantitative ADAM questionnaire: a new tool in quantifying the severity of hypogonadism.

Androgen deficiency is a pervasive problem in the older male population and is thought to be responsible for many symptoms once considered to be the result of normal aging. Numerous methods have been proposed to facilitate the detection of men at risk for androgen deficiency. In this article, we propose a novel screening tool, the quantitative Androgen Deficiency in the Aging Male (qADAM) questionnaire and report its successful use in quantifying the severity of androgen deficiency in a group of older men. Fifty-seven males scheduled to undergo radical prostatectomy for prostate cancer completed the qADAM as well as the Sexual Health Inventory for Men (SHIM) and the Expanded Prostate Cancer Index Composite hormonal/sexual (EPICh/EPICs) questionnaires. Thirty-four men also had serum testosterone levels measured for comparison. The qADAM showed statistically significant correlation to the SHIM (P=0.001), EPICh (P=0.016), EPICs (P= <0.001), and serum testosterone (P=0.046). The qADAM represents a viable alternative to existing questionnaires used to detect androgen deficiency and to assess response to treatment.

Research productivity of the medical faculty at the American University of Beirut.

OBJECTIVE: To analyse the quality and quantity of scientific publications of the medical faculty at the American University of Beirut (AUB) during a six year period (1996-2001) METHODS: The study included all faculty members in the medical school of AUB in the year 2001. A Medline search inclusive of the years 1996-2001 was done for each faculty member and a total number of 881 publications was obtained. RESULTS: The faculty consisted of 203 members. Their average productivity rate (mean (SD)) was 1.24 (1.38) publications/faculty member/year (PFY), with a mean impact factor of 2.69 (4.63). Eighteen per cent of the faculty did not have any publication in the six year study period, and only 20% had two or more publications per year. There was a significantly higher publication rate among newly recruited faculty members (0.93 (1.40) PFY for those appointed before 1990, 1.45 (1.24) PFY for those appointed during 1990-1995, and 1.67 (1.43) for those appointed after 1995, p = 0.007), and among those who are younger in age (p<0.01). Collaboration with international investigators resulted in more original publications than work done only at AUB (65% v 35%, p<0.001), and a higher journal impact factor for the publications (3.20 (3.85) v 1.71 (2.36), p<0.05). CONCLUSIONS: This is one of the first studies that analyse the research productivity of the medical faculty in a university setting in a developing country. It shows a wide variation in the research productivity of the faculty members that seems to be related to individual as well as institutional characteristics. Further analysis is needed to define and characterise these factors.

Myocardial perfusion and angiographic correlations in patients with ST-segment elevation during dobutamine stress perfusion imaging.

BACKGROUND: There is scanty information on the angiographic and myocardial perfusion correlates of dobutamine-induced ST-segment elevation. METHODS AND RESULTS: We studied 39 patients who exhibited ST-segment elevation during dobutamine perfusion tomography and had recent coronary angiography performed (ie, within 3 months of the dobutamine study). Baseline characteristics, extent of coronary artery disease, relationship of Q waves to ST-segment elevation, ischemic burden, and angiographic findings were assessed. Twenty-nine patients (74%) had prior myocardial infarction, and 77% had abnormal Q waves at baseline. Ninety-three percent of patients had abnormal perfusion imaging. Eighty percent of patients had multivessel coronary artery disease. The left ventricular ejection fraction by contrast ventriculography was 35% +/- 7% (mean +/- SD), the perfusion defect size was 32% +/- 15%, and 73% of patients had some degree of myocardial ischemia. A predominance of ischemia (>50% reversibility) occurred in 38% of patients with Q waves and in 70% of those without Q waves. There was also good agreement between the site of ST-segment elevation and the site of ischemia by perfusion imaging (79%) and between the site of ST-segment elevation and the location of the vessel with significant coronary stenosis (95%). CONCLUSIONS: Patients with dobutamine-induced ST-segment elevation have a depressed left ventricular ejection fraction, a high frequency of multivessel disease, and markedly abnormal myocardial perfusion tomography. In patients with ST-segment elevation and abnormal Q waves, substantial scarring and superimposed ischemia coexist, whereas in patients without Q waves, ST-segment elevation usually denotes severe ischemia.

Chest pain evaluation.

Chest pain is one of the frequent complaints in patients presenting to emergency rooms and ambulatory care clinics. For the primary care physician evaluating these patients, there are three essential steps in the evaluation of chest pain. The first step is to determine whether the chest pain is cardiac in origin or not. If the pain is suspected to be cardiac, then the next step would be to determine if the chest pain is secondary to an acute coronary syndrome (acute myocardial infarction or unstable angina) that requires immediate referral to an emergency room to initiate therapy and admit to the hospital. If the pain is not considered to be due to an acute coronary syndrome, then we proceed with a systematic approach to try to determine the likelihood that a particular patient has significant coronary artery disease (CAD). This is determined based on the patient's history, risk factors and electrocardiogram. Once the likelihood is assessed, this will determine what further invasive or non-invasive tests would be required to complete the patient's evaluation.

Repeated doses of tissue plasminogen activator for failed thrombolysis: case report and review of the literature.

This article reports the first case of a patient presenting with acute myocardial infarction in whom a repeated dose of tissue plasminogen activator (t-PA) was able to achieve successful thrombolysis after a first dose of t-PA itself failed to do so. This case report presents an alternative approach for the treatment of patients who fail thrombolysis after an initial dose of t-PA, an approach that might be particularly useful in hospitals that do not have immediate access to advanced interventional services.

Use of invasive and nuclear stress testing in patients with acute ischemic coronary syndromes in a large, urban, university-affiliated hospital.

BACKGROUND: Several recent studies have suggested a high use of invasive procedures after acute myocardial infarction, without a corresponding improvement in survival. We assessed the relative use of invasive procedures and nuclear cardiac testing during acute coronary syndromes. METHODS AND RESULTS: We examined the in-hospital utilization rates of invasive and nuclear stress tests and their association with in-hospital mortality in all patients hospitalized with an acute coronary syndrome in a single, university-affiliated hospital for 3 years. The study cohort consisted of 1704 consecutive patients with acute myocardial infarction and 2414 patients with unstable angina pectoris. The utilization rate of nuclear stress testing was much lower than that of coronary angiography in patients with either acute myocardial infarction (11.9% vs. 73.9%, P<.001) or unstable angina (8.5% vs. 79.3%, P<.001). Patients examined with nuclear stress testing, as compared with patients examined solely by means of coronary angiography, had lower revascularization and in-hospital mortality rates, both after acute myocardial infarction (29.2% vs. 70%, P<.001, and 1.5% vs. 9.6%, P<.001, respectively) and unstable angina (14.6% vs. 80.6%, P<.001, and 1% vs. 5.1%, P<.001, respectively). Revascularization guided by means of nuclear stress testing had a lower mortality rate than that performed without the benefit of a nuclear test, both in patients with acute myocardial infarction (0% vs. 10.5%) and in patients with unstable angina (0% vs. 5.9%). CONCLUSION: Noninvasive stress imaging was used much less often than coronary angiography in patients with acute coronary syndromes. The lower mortality rate of patients examined with nuclear stress testing, compared with patients examined solely by means of coronary angiography, deserves further study, especially in patients undergoing revascularization.

Cox-Maze procedure for treatment of atrial flutter associated with an atrial septal defect.

A 52-year-old man presented with atrial flutter and was found to have an atrial septal defect (ASD). The paper describes an effective surgical approach for the treatment of this atrial arrhythmia utilizing a right sided Cox-maze III procedure concomitant with ASD closure. Review of the literature and clinical implications are discussed.

Long-term prognostic value of exercise echocardiography compared with exercise 201Tl, ECG, and clinical variables in patients evaluated for coronary artery disease.

BACKGROUND: The accuracy of exercise echocardiography and 201Tl single photon emission computed tomography (SPECT) is similar in the diagnosis of coronary artery disease (CAD). However, comparative data on long-term prognosis are lacking. METHODS AND RESULTS: Clinical variables and exercise, echocardiographic, and 201Tl tomographic parameters were studied in 248 patients (age, 56+/-12 years [mean+/-SD]; 189 men) who underwent simultaneous treadmill exercise 201Tl SPECT and echocardiography. Follow-up was obtained in 225 patients (91%) at a mean of 3.7+/-2.0 years. A total of 64 cardiac events occurred. With the use of stepwise logistic regression, 4 models simulating clinical stress testing scenarios were evaluated in the prediction of all cardiac events, ischemic events, and/or cardiac death. The best clinical models were exercise echocardiography with exercise ECG and exercise 201Tl SPECT with exercise ECG. Both models were comparable in the prediction of cardiac events. For the exercise echocardiography model, exercise wall motion score index and induction of ischemia were the strongest predictors of events with ORs of 2.63 per unit increment (95% CI, 1. 34 to 5.17; P=0.005) and 4.1 (95% CI, 1.32 to 12.79; P=0.015), respectively. For the model with exercise 201Tl SPECT, the strongest predictor was ischemic perfusion defect (OR, 4.93; 95% CI, 1.72 to 14.08; P=0.003). The absence of ST changes during exercise decreased the risk of events. For the prediction of ischemic events and/or cardiac death, echocardiographic and 201Tl parameters were the only predictive variables. CONCLUSIONS: In patients evaluated for CAD, exercise echocardiography and 201Tl combined with ECG variables provide comparable prognostic information and can be used interchangeably for risk stratification.

Intensive medical therapy versus coronary angioplasty for suppression of myocardial ischemia in survivors of acute myocardial infarction: a prospective, randomized pilot study.

BACKGROUND: Patients who have inducible ischemia after acute myocardial infarction (AMI) generally undergo coronary angiography with the intent to revascularize. Whether this approach is superior to intensive treatment with anti-ischemic medications is unknown. METHODS AND RESULTS: We performed a prospective, randomized pilot study comparing intensive medical therapy with coronary angioplasty (PTCA) for suppression of myocardial ischemia in 44 stable survivors of AMI. Myocardial ischemia was quantified with adenosine 201Tl tomography (SPECT) performed 4.5+/-2.9 days after AMI. All patients at baseline had a large total (>/=20%) and ischemic (>/=10%) left ventricular perfusion defect size (PDS). SPECT was repeated at 43+/-26 days after therapy was optimized. The total stress-induced PDS was comparably reduced with medical therapy (from 38+/-13% to 26+/-16%; P<0.0001) and PTCA (from 35+/-12% to 20+/-16%; P<0.0001). The reduction in ischemic PDS was also similar (P=NS) in both groups. Cardiac events occurred in 7 of 44 patients over 12+/-5 months. Patients who remained clinically stable had a greater reduction in ischemic PDS (-13+/-9%) than those who had a recurrent cardiac event (-5+/-7%; P<0.02). Event-free survival was superior in the 24 patients who had a significant (>/=9%) reduction in PDS (96%) compared with those who did not (65%; P=0.009). CONCLUSIONS: In this small pilot study, intensive medical therapy and PTCA were comparable at suppressing ischemia in stable patients after AMI. Sequential imaging with adenosine SPECT can track changes in PDS after anti-ischemic therapies and thereby predict subsequent outcome. Corroboration of these preliminary findings in a larger cardiac-event trial is warranted.

Assessment of myocardial viability with 99mTc-sestamibi tomography before coronary bypass graft surgery: correlation with histopathology and postoperative improvement in cardiac function.

BACKGROUND: Assessment of myocardial viability by 99mTc-sestamibi remains controversial. Accordingly, we investigated the use of sestamibi as a marker of myocardial viability, defined by histopathology, and for predicting improvement of myocardial function after coronary artery bypass graft surgery (CABG). METHODS AND RESULTS: 99mTc-sestamibi perfusion tomography and radionuclide angiography were performed within 2 days before CABG in 21 patients with > or = 75% stenosis of the left anterior descending coronary artery and resting anterior wall dyssynergy. During CABG, transmural myocardial biopsies were obtained from the dyssynergic anterior wall and from normal myocardial segments to determine the extent of viable myocardium by histopathology. Improvement of regional left ventricular function was evaluated by radionuclide angiography at 6 to 8 weeks after CABG. There was a good correlation (r=.85, P<.001) between the quantified sestamibi activity and the extent of viable myocardium determined morphometrically. Among 21 biopsied dyssynergic myocardial segments, 11 improved their function after CABG and 10 failed to improve. Biopsied segments with improved postoperative function had significantly higher sestamibi activity (81+/-5% versus 49+/-16%, P<.0001) and significantly lower extent of interstitial fibrosis (7+/-4% versus 31+/-21%, P=.0002) than segments that failed to improve. A 55% threshold of 99mTc-sestamibi activity had positive and negative predictive values of 79% and 100%, respectively, for recovery of function after CABG in the biopsied segments. CONCLUSIONS: Myocardial 99mTc-sestamibi activity correlates well with the extent of viable myocardium and predicts improvement in regional function after CABG. This lends support to the use of sestamibi as a myocardial viability agent.

Association of angiotensin I-converting enzyme gene polymorphism with myocardial ischemia and patency of infarct-related artery in patients with acute myocardial infarction.

OBJECTIVES: We determined the influence of angiotensin I-converting enzyme (ACE) insertion (I)/deletion (D) polymorphism on the extent of myocardial ischemia in patients with acute myocardial infarction. BACKGROUND: The I/D polymorphism, which in part controls plasma and tissue expression of ACE, has been implicated in predisposition to myocardial infarction and ventricular remodeling. METHODS: I/D genotyping, predischarge adenosine-thallium-201 perfusion tomography and radionuclide angiography were performed in 113 patients (72 men, 41 women) with a diagnosis of acute myocardial infarction. A subgroup of 96 patients also underwent coronary angiography. RESULTS: Genotypes DD, ID and II were present in 27, 56 and 30 patients, respectively. There was no significant difference in the baseline characteristics of patients, total creatine kinase, peak MB fraction, Killip class, mean ejection fraction or the number of diseased vessels in patients with the DD, ID or II genotype. However, the size of the total and the reversible perfusion defects was greater in those with DD than in those with ID or II genotype (total defect size [mean +/- SD] 33.7 +/- 22.5%, 29.5 +/- 19.2% and 22.2 +/- 16.0%, respectively [p = 0.022]; reversible defect size 18.0 +/- 16.0%, 12.1 +/- 11.6% and 8.2 +/- 7.8%, respectively [p = 0.006]). Occlusion of the infarct-related artery was also more common in patients with DD genotype (odds ratio 3.9, 95% confidence interval 1.4 to 11.0). Multivariate analysis showed that the I/D genotype was an independent predictor of perfusion defect size and patency of the infarct-related artery (p = 0.001). CONCLUSIONS: DD genotype was associated with a larger ischemic defect and occlusion of the infarct-related artery. Patients with DD genotype, having a larger ischemic defect, are expected to be at a greater risk for subsequent cardiovascular events.

Prognostic value of exercise 201Tl tomography in patients treated with thrombolytic therapy during acute myocardial infarction.

BACKGROUND: Although myocardial perfusion scintigraphy is of proven value in the risk stratification of patients with a recent myocardial infarction who receive conventional therapy, its value in patients undergoing thrombolytic therapy remains controversial. METHODS AND RESULTS: Seventy-one patients who received thrombolytic therapy for acute myocardial infarction had exercise 201Tl tomography and coronary angiography before hospital discharge. Eleven (15%) of 71 patients had ischemic ST-segment depression during exercise, whereas 27 patients (38%) had scintigraphic ischemia. Twenty-five (37%) of 68 patients had a cardiac event consisting of either death (n = 2), recurrent myocardial infarction (n = 5), congestive heart failure (n = 7), or unstable angina (n = 11) during a follow-up of 26 +/- 18 months. Univariate predictors of cardiac events were as follows: Killip class (P = .04); left ventricular ejection fraction (P < .0005); total (P = .002) and ischemic (P < .0005) perfusion defect size; percent thallium lung uptake (P = .001); presence of infarct-zone redistribution (P = .02); and multivessel coronary artery disease (P = .01). By multivariate analysis, the significant joint predictors of risk were ejection fraction (P < .0005) and ischemic perfusion defect size (P = .005). The combination of ejection fraction and thallium tomography added significant incremental prognostic information to the clinical data, whereas angiography did not further improve a model that included clinical, ejection fraction, and tomographic variables. CONCLUSIONS: Quantitative exercise 201Tl tomography provides important incremental, long-term prognostic information in patients receiving thrombolytic therapy for acute myocardial infarction.

Tolerance, hemodynamic changes, and safety of dobutamine stress perfusion imaging.

BACKGROUND: Dobutamine myocardial perfusion imaging is being used increasingly for assessment of coronary artery disease. Heretofore, there have been no large series documenting its tolerance and safety. The aims of this study were to assess the tolerance, hemodynamic changes, and safety of dobutamine stress in conjunction with myocardial perfusion imaging. METHODS AND RESULTS: The tolerance, hemodynamic changes, and safety of dobutamine myocardial perfusion imaging were investigated in a consecutive series of 1012 patients. Dobutamine was infused at incremental doses of 10, 20, 30, and 40 micrograms/kg/min at 3-minute intervals. Perfusion tomography was performed according to standard protocols with either 201Tl or 99mTc-labeled sestamibi. Seven hundred twenty-nine patients (72%) reached a maximal dobutamine dose of 40 micrograms/kg/min. Dobutamine significantly increased heart rate (76 +/- 14 beats/min to 127 +/- 20 beats/min; p < 0.001) and systolic blood pressure (141 +/- 20 mm Hg to 168 +/- 36 mm Hg; p < 0.001) from baseline to peak infusion rate. The most common side effects were chest pain (31%), headache (14%), dyspnea (12%), palpitations (10%), and flushing (10%). There was no death, myocardial infarction, pulmonary edema, ventricular fibrillation, sustained ventricular tachycardia, or cerebral vascular accident. Nonsustained ventricular tachycardia occurred in 43 patients (4.2%) but did not cause any hemodynamic instability. CONCLUSIONS: When done with the necessary caution, dobutamine myocardial perfusion imaging is a safe diagnostic test, although side effects are common.