Thyroid hormone upregulates MDM2 in rat type I fibre: Implications for skeletal muscle mass regulation.

AIM: Based upon a microarray assay, we have identified that triiodothyronine (T3) upregulates MDM2 gene expression in the rat skeletal muscle. As MDM2 protein is an E3 ligase, we hypothesized that this enzyme could play a role in T3 effects on skeletal muscle mass control. METHODS: To test our hypothesis, male rats (2 months old) were randomly assigned into the following groups: intact controls, treated with 20 physiological doses of T3 for 0.5, 1 and 7 days, or with 5, 20 and 50 physiological doses of T3 for 7 days. For in vitro experiments, myotubes and C2C12 cells were treated with T3 for 3 days. RESULTS: After validation of the microarray finding throughout RT-PCR and confirmation that T3 induces increases in MDM2 protein expression in a dose-dependent manner, we observed that MDM2 was upregulated by T3 exclusively in fibre type I. Moreover, detailed histological evaluation showed that MDM2 overexpression distributes punctiformily along the cross section of the fibre and also inside nuclei. MDM2 colocalizes with PAX7 in control muscle and T3 downregulates this myogenic factor. Pharmacological inhibition of MDM2 in cultured myotubes caused a severe decrease in their diameter (~35%, P < .001 vs Control), enhancing the effect of T3 (from ~12% to ~35%, P < .001) alone upon myotube diameter and mRNA levels of atrogenes. Finally, we observed that FOXO3 (MDM2 target) is kept outside the nucleus under T3 stimulation. CONCLUSION: Our results indicate that MDM2 might be involved in the pro-trophic effects of T3 in skeletal muscle.

SPECT/PET myocardial perfusion imaging versus coronary CT angiography in patients with known or suspected CAD.

Stress SPECT myocardial perfusion imaging (MPI) is the most commonly utilized stress imaging technique for patients with suspected or known coronary artery disease (CAD) and has a robust evidence base including the support of numerous clinical guidelines. Gated SPECT is a well-established noninvasive imaging modalities that is a core element in evaluation of patients with both acute and stable chest pain syndromes. Over the past decade, PET has become increasingly used for the same applications. By comparison, cardiac computed tomography (CT) is a more recently developed method, providing non-invasive approaches for imaging coronary atherosclerosis and coronary artery stenosis. Non-contrast CT for imaging the extent of coronary artery calcification (CAC), in clinical use since the mid-1990's, has a very extensive evidence base supporting its use in CAD prevention. While contrast-enhanced CT for noninvasive CT coronary angiography (CCTA) is relatively new, it has already developed an extensive base of evidence regarding diagnosing obstructive CAD and more recently evidence has emerged regarding its prognostic value. It is likely that non-contrast CT or CCTA for assessment of extent of atherosclerosis will become an increasing part of mainstream cardiovascular imaging practices as a first line test. In some patients, further ischemia testing with MPI will be required. Similarly, MPI will continue to be widely used as a first-line test, and in some patients, further anatomic definition of atherosclerosis with CT will also be appropriate. This review will provide a synopsis of the available literature on imaging that integrates both CT and MPI in strategies for the assessment of asymptomatic patients for their atherosclerotic coronary disease burden and risk as well as symptomatic patients for diagnosis and guiding management. We propose possible strategies through which imaging might be used to identify asymptomatic candidates for more intensive prevention and risk factor modification strategies as well as symptomatic patients who would benefit from referral to invasive coronary angiography for consideration of revascularization.

The quality of life of patients on the lung transplantation waiting list.

INTRODUCTION: Lung transplantation (LTx) candidates present incapacitating symptoms related to their mobility and activities of daily living, thereby affecting their work, social and emotional relations, and quality of life (QoL). OBJECTIVE: To study the QoL of LTx candidates, seeking to identify domains that suffer the greatest impact and verify if there are differences among these impairments according to the original lung disease. METHODS: We applied the Short Form-36 questionnaires and St George's Respiratory Questionnaire (SGRQ). All data were analyzed by one-way analysis of variance and the Kruskal Wallis test for the probability with significance at P < 0.05. RESULTS: Fifty patients were divided into groups of emphysema (n = 16), bronchiectasis (n = 12), idiopathic pulmonary fibrosis (n = 7), and cystic fibrosis (n = 15). The functional capacity, physical aspects, general status, and vitality domains showed average values below 50 points. The cystic fibrosis group showed higher functional capacity scores (46 +/- 23) than the emphysema (12 +/- 13) or idiopathic pulmonary fibrosis cohort (7 +/- 5). The limitation caused by pain affected the bronchiectasis more than the cystic fibrosis group (52 +/- 28 vs 81 +/- 25, respectively). The SGRQ scores showed impairment among all groups in all domains with average values over 50. The activities domain shows the highest score value; the emphysema (92 +/- 10) and idiopathic pulmonary fibrosis cohorts (91 +/- 9) were extremely affected compared with the cystic fibrosis (69 +/- 21) and bronchiectasis subjects (79 +/- 16). The impact domain show that subjects with cystic fibrosis were less emotionally affected by the disease. CONCLUSION: LTx candidates showed great impairment of their QoL due to their health problems, above all in the physical-functional aspects; the cystic fibrosis patients were the least affected by their health status.

Synthesis, molecular modelling, and antiproliferative and cytotoxic effects of carbocyclic derivatives of distamycin with chlorambucil moiety.

New carbocylic analogues of distamycin and netropsin with chlorambucil moieties 5-8 have been synthesised. Data from the ethidium displacement assay showed that these compounds bind in the minor groove of DNA. The observed reduced affinity to AT pairs and increased affinity towards GC sequences of the carbocyclic lexitropsins with chlorambucil moiety 5-8 in comparison with netropsin and distamycin was observed and rationalised by means of molecular modelling techniques. All of the compounds 5-8 showed antiproliferative and cytotoxic effects in the standard cell line of the mammalian tumour MCF-7.

Peripheral arterial responses to treadmill exercise among healthy subjects and atherosclerotic patients.

UNLABELLED: BACKGROUND-Peripheral cutaneous vascular beds, such as the fingertips, contain a high concentration of arteriovenous anastomoses, richly innervated by a-adrenergic nerve fibers, to control heat regulation. Nevertheless, for a variety of technical reasons, finger blood flow responses to exercise have not been well studied in health and disease. Hence, we compared finger pulse-wave amplitude (PWA) responses to exercise among 50 normal volunteers and 57 patients with atherosclerotic coronary artery disease (CAD) using a robust, modified form of volume plethysmography. METHODS AND RESULTS: PWA was quantified for each minute of exercise as a ratio relative to baseline. Exercise PWA responses were compared with clinical, hemodynamic, ECG, and myocardial single photon emission computed tomography parameters. Among normal subjects, 38 (76%) manifested vasodilation throughout exercise and 12 (24%) manifested initial vasodilation followed by vasoconstriction at high heart rate thresholds. None manifested vasoconstriction throughout exercise. By contrast, 20 CAD patients (35%) manifested progressive vasoconstriction from the onset of exercise, and 10 others (18%) manifested vasoconstriction at low heart rate thresholds (P < 0.001 versus normals) after initial vasodilation with exercise. Patients exhibiting vasodilation versus vasoconstriction during exercise had similar clinical and exercise profiles, except for a greater use of ACE inhibitors and a greater level of achieved metabolic equivalents among the former (P<0.05 for both). CONCLUSIONS: Half of our CAD patients manifested diminution in PWA that was consistent with peripheral arterial vasoconstriction during the early phases of treadmill exercise. Such paradoxical vasoconstrictive responses were not observed in normal subjects and, therefore, they may represent generalized vascular pathology secondary to atherosclerosis.

Principal uses of myocardial perfusion scintigraphy in the management of patients with known or suspected coronary artery disease.

The use of myocardial perfusion single photon emission computed tomography (SPECT) has undergone considerable expansion and evolution over the past 2 decades. Although myocardial perfusion imaging was first conceived as a noninvasive diagnostic tool for determining the presence or absence of coronary artery disease, its prognostic value is now well established. Thus, identification of patients at risk for future cardiac events has become a primary objective in the noninvasive evaluation of patients with chest pain syndromes and among patients with known coronary artery disease. In particular, the ability of myocardial perfusion SPECT to identify patients at low (< 1%), intermediate (1% to 5%) or high (> 5%) risk for future cardiac events is essential to patient management decisions. Moreover, previous studies have conclusively shown the incremental prognostic value of myocardial perfusion SPECT over clinical and treadmill exercise data in predicting future cardiac events. This report addresses the current role and new developments, with respect to the use of myocardial perfusion imaging, in determining patient risk for cardiac events and the cost-effective integration of such information into patient management decisions.

Stress radionuclide imaging versus stress echocardiography: a framework for comparisons.

Comparisons of stress-imaging procedures require analyses based on their 2 principal applications: diagnostic and prognostic assessments. Besides comparing results reported in the literature--in which differences have been reported in the ability of stress nuclear versus stress echocardiographic imaging to predict a low risk of cardiac events-other factors often not reported may be important in discerning the relative efficacy of these tests. These include consideration of how these tests perform in specific, individualized patient scenarios; the effect of on-going technical advances on test usefulness; and evaluation of test worthiness according to such factors as cost-effectiveness and the magnitude of incremental test information that is provided. Furthermore, it is important to distinguish between a test's efficacy (ie, its intrinsic accuracy) and its effectiveness (ie, how it performs in the real world of clinical practice).

Postexercise left ventricular function: a comparative assessment by different noninvasive imaging modalities.

The variety of noninvasive imaging modalities now available permits assessment of different aspects of left ventricular function in the postexercise state. Some of these modalities, such as first-pass radionuclide ventriculography, permit a nearly instantaneous assessment of left ventricular function in the early postexercise state. These modalities indicate that most exercise-induced left ventricular wall motion abnormalities resolve quickly after exercise. Resting wall motion abnormalities may also improve in the postexercise period; this response indicates the presence of hibernating myocardium capable of improving in response to myocardial revascularization procedures. On the other hand, all imaging techniques indicate that a certain percentage of exercise-induced wall motion abnormalities may persist into the postexercise period, and this finding signifies that severe coronary disease subtends the region of persisting wall motion abnormality. Further, if there is increased left ventricular size after exercise, both extensive and severe coronary disease are present. A conceptual framework for unifying these disparate findings is provided. These results underscore the importance of postexercise imaging in enhancing clinical assessment and imply that there are important technical considerations to contemplate when performing certain tests such as postexercise echocardiography.

Principles for combining radionuclide and echocardiographic stress imaging into a single clinical laboratory service.

Physicians who supervise stress-imaging procedures, whether they be stress nuclear or stress echocardiography tests, are increasingly required to incorporate important principles in the interpretation of the test results. Important guiding principles, common to these tests, are reviewed in this article. The principles include the following: avoiding categorical interpretation of test results; identifying equivocal test responses; combining diagnostic and prognostic information in rendering information to referring physicians; integrating the stress test results with other clinical data and using Bayesian analysis as a decision-aid; reporting one's confidence in the interpretation of the results of testing; characterizing both the extent and severity of any induced myocardial ischemia; and analyzing the test results in a blinded fashion, without prior knowledge of patient clinical history

Aryltriazole C-nucleosides with affinity to certain DNA sequence. II. Synthesis of 4-(beta-D-erythrofuranosyl)-2-(4-methyl-3-nitrophenyl)-1,2,3-triazole from D-psicose.

The paper describes the synthesis of 4-(beta-D-erythrofuranosyl)-2-(4-methyl-3-nitrophenyl)-1,2,3-triazole. This compound is a starting material for synthesis of C-nucleosides, having a potential affinity with G-C base pair.

Development and application of normal limits for left ventricular ejection fraction and volume measurements from 99mTc-sestamibi myocardial perfusion gates SPECT.

UNLABELLED: Gated SPECT is a reproducible method for assessing left ventricular volume (LVV) and left ventricular ejection fraction (LVEF) from 99mTc-sestamibi myocardial perfusion imaging studies. LVV and LVEF measurements by this approach correlate well with those obtained from other cardiovascular imaging techniques. Nevertheless, the lack of criteria for abnormal test findings has limited the potential clinical application of this new imaging technique. METHODS: Gated SPECT measurements were evaluated for 214 patients with a low Bayesian likelihood (< 10%) of coronary artery disease (CAD) before performance of 99mTc-sestamibi stress-rest myocardial perfusion SPECT. The patients were grouped into normotensive patients (n = 98), hypertensive patients without left ventricular hypertrophy (LVH) (n = 80), and hypertensive patients with LVH on resting electrocardiography (n = 36). Gated SPECT measurements for left ventricular end-diastolic volume (LVEDV) index, left ventricular end-systolic volume (LVESV) index, and LVEF were obtained according to a published method, using a modified Simpson's rule technique. RESULTS: Similar results were obtained for mean LVV and LVEF measurements between normotensive patients and hypertensive patients without LVH. Hence, these groups were combined (as group 1). By contrast, hypertensive patients with LVH (group 2), had significantly lower LVEF values (P = 0.01) and higher mean LVESV index values than normotensive patients (P = 0.03). Sex differences were marked: women had significantly higher mean resting LVEF values than men (P < 0.0001) and significantly lower mean resting LVEDV index values (P < 0.0001). A significant relationship was seen between LVEDV index and LVEF (r = -0.60; P < 0.0001) and between LVEDV index and heart rate (r = -0.26; P < 0.001). The normal limits were LVEF > or = 41% in men and > or = 49% in women, LVEDV index < or = 76 mL/m2 in men and < or = 57 mL/m2 in women, and LVESV index < or 38 mL/m2 in men and < or =26 mL/m2 in women. Among hypertensive patients, 22% with LVH had an abnormally low LVEF and 19% had an increased LVEDV index according to these test criteria. By contrast, no hypertensive patients without LVH had an abnormally low LVEF, and only 6% had volume abnormalities. CONCLUSION: Using a cohort of low-likelihood patients, we generated sex-specific normal limits for LVV and LVEF for myocardial perfusion gated SPECT. Application of these findings resulted in the detection of occult left ventricular dysfunction in approximately one fifth of hypertensive patients for whom concomitant LVH was found through resting electrocardiography. These normal limits can now be evaluated prospectively for their potential clinical value.

Molecular modelling, synthesis and antitumour activity of carbocyclic analogues of netropsin and distamycin--new carriers of alkylating elements.

A series of netropsin and distamycin analogues was synthesised and investigated by molecular modelling. The lowest-energy conformations of four carbocyclic lexitropsins, potential carriers of alkylating elements, were obtained using the HyperChem 4.0 program, and compared with the DNA-lexitropsin crystal structures from the Brookhaven National Laboratory Protein Data Bank. A method for synthesis of carbocyclic lexitropsins was elaborated, with the use of a nitro group or azobenzene as precursors for the aromatic amino group. The influence of methoxy group in ortho position with respect to amide groups on the activity of the new compounds was investigated. All of the compounds tested showed high antitumour activity in the standard cell line of mammalian tumour MCF-7.

Echocardiographic validation of gated SPECT ventricular function measurements.

UNLABELLED: Left ventricular (LV) volumes are valuable prognostic indicators in the management of coronary artery disease and traditionally have been obtained by x-ray contrast angiography or echocardiography. There now are several scintigraphic methods to compute volumes that are based on different LV modeling assumptions. Both the reasons that calculations from different nuclear techniques can disagree with one another and the relationship of these values to the more conventional echocardiographic measurements must be investigated thoroughly for calculations to be interpretable for individual patients. METHODS: Echocardiographic volumes were determined in 33 retrospective subjects with coronary artery disease (mean age, 61 +/- 12 y; 42% men; 70% with abnormal perfusion and 58% with abnormal segmental wall motion) using the modified Simpson's rule technique applied to digitized apical 4-chamber and apical 2-chamber views of 4 averaged heartbeats. These volumes were compared with those from 3 gated SPECT methods based on Simpson's rule LV modeling similar to standard echocardiographic algorithms (SPECT EF from St. Luke's-Roosevelt Hospital) (method 1), Gaussian myocardial count profile curve fitting (QGS from Cedars-Sinai Medical Center) (method 2), and an endocardial model based on perfusion sampling and count-based thickening (Cardiac Toolbox from Emory University) (method 3). RESULTS: By ANOVA, there were no significant differences among ejection fractions (EFs), but there were for volumes. Paired t test analysis showed volumes from methods 2 and 3 to be significantly larger than echocardiographic volumes and larger than those of method 1. Linear regression analysis comparing gated SPECT and echocardiographic volumes showed a nearly identical strong correlation (r = 0.92; P < 0.000001) for all 3 methods. Excellent correlation also was found among gated SPECT volumes from the 3 methods (r = 0.94). Bland-Altman analysis and t tests showed that method 1 volumes (70 +/- 61 mL) were the same as for echocardiography (77 +/- 55 mL), but volumes were overestimated by method 2 (105 +/- 74 mL) and method 3 (127 +/- 92 mL), particularly for larger volumes. Pearson coefficients for EFs compared with echocardiography were r = 0.82, 0.75, and 0.72 for methods 1-3, respectively. EFs correlated strongly among the 3 gated SPECT methods (r = 0.86-0.92). The Fisher z test showed no differences among these methods for any of the volume or EF linear correlation analyses. CONCLUSION: All gated SPECT parameters correlated well with echocardiographic values. However, the gated SPECT method for which underlying assumptions most closely resembled those commonly used in echocardiography produced mean volume values closest in agreement with echocardiographic measurements.

Pyrrole analogues of chloramphenicol. I. Synthesis and antibacterial activity of DL-threo-1-(1-methyl-4-nitropyrrole-2-yl)-2-dichloroacetamidopropane-1,3-diol.

The seven-stage synthesis of a pyrrole analogue of chloramphenicol [IX] was described. The compound exhibits a significant antibacterial activity, over the 12-50% range of the chloramphenicol activity.

Pyrrole analogues of chloramphenicol. II. Synthesis and antibacterial activity of DL-threo-1-(1-methyl-5-nitro-pyrrole-2-yl)-2-dichloroacetamidopropane-1, 3-diol.

The seven-stage synthesis of a pyrrole analogue of chloramphenicol (VII) was described. The compound exhibits a significant antibacterial activity.

Synthetic analogues of netropsin and distamycin. VI. Synthesis of carbocyclic lexitropsins containing a bioreductive element.

Carbocyclic derivatives of lexitropsines containing of two aromatic rings, N-dimethylaminopropyl group lonked to carboxyl terminus and 5-[bis(2-chloroethyl)-amino]-2,4-dinitrobenzamide group linked to the amino terminus group were synthesed. The N-terminal group should present selective alkylating activity on the DNA of cancer cells in conditions of hypoxia.

Molecular modelling of the interaction of carbocyclic analogues of netropsin and distamycin with d(CGCGAATTCGCG)2.

A molecular mechanics and molecular dynamics approach was used to examine the structure of complexes formed between the d(CGCGAATTCGCG)2 duplex and netropsin, distamycin, and four carbocyclic analogues of netropsin and distamycin (1-4). The resulting structures of the ligand-DNA model complexes and their energetics were examined. It is predicted that the compounds 1-4 should have a decreased affinity for the minor groove of AT-rich regions in comparison to netropsin and distamycin. From the energetic analysis it appears that van der Waals and electrostatic interactions are more important than specific hydrogen bonds in stabilizing the ligand-duplex complexes. We predict that compounds 1 and 2 are effectively isohelical with the DNA minor groove. The superior DNA-binding afforded by 1 and 2 in comparison to 3 and 4 results from their more effective penetration into the minor groove and smaller perturbation of molecular structure upon complex formation.

Prognostic value of mental stress testing in coronary artery disease.

This study assesses the prognostic value of mental stress-induced ischemic left ventricular wall motion abnormalities and hemodynamic responses in patients with stable coronary artery disease (CAD). Seventy-nine patients (76 men and 3 women) with prior positive exercise test results were exposed to mental arithmetic and a simulated public speech stress in 2 prior studies. Ischemic wall motion abnormalities were monitored using echocardiography or radionuclide ventriculography (RNV). During mental stress testing, new or worsened ischemic wall motion abnormalities to mental stress and exercise were ascertained, as were peak changes in blood pressure and heart rate to mental stress. The occurrence of subsequent cardiac events (including cardiac death, nonfatal myocardial infarction, or revascularization procedures) was ascertained. New cardiac events were observed in 28 of 79 patients (35%) after a median follow-up duration of 3.5 years (range 2.7 to 7.3). Survival analysis indicated that 20 of 45 patients with mental stress ischemia (44%) experienced new cardiac events more frequently than those without mental stress ischemia (8 of 34; 23%; p = 0.048). Type of cardiac event did not differ between mental stress-positive and stress-negative patients. After controlling for baseline blood pressure and study group status (echocardiography vs RNV), there was a significantly higher relative risk of subsequent events for patients with high versus low peak stress-induced diastolic blood pressure responses (RR = 2.4, confidence interval 1.1 to 5.2; p = 0.03). These results demonstrate that ischemic and hemodynamic measures obtained from mental stress testing may be useful in assessing prognosis in CAD patients with prior positive exercise test results.