HIV replication enhances production of free fatty acids, low density lipoproteins and many key proteins involved in lipid metabolism: a proteomics study.

BACKGROUND: HIV-infected patients develop multiple metabolic abnormalities including insulin resistance, lipodystrophy and dyslipidemia. Although progression of these disorders has been associated with the use of various protease inhibitors and other antiretroviral drugs, HIV-infected individuals who have not received these treatments also develop lipid abnormalities albeit to a lesser extent. How HIV alters lipid metabolism in an infected cell and what molecular changes are affected through protein interaction pathways are not well-understood. RESULTS: Since many genetic, epigenetic, dietary and other factors influence lipid metabolism in vivo, we have chosen to study genome-wide changes in the proteomes of a human T-cell line before and after HIV infection in order to circumvent computational problems associated with multiple variables. Four separate experiments were conducted including one that compared 14 different time points over a period of >3 months. By subtractive analyses of protein profiles overtime, several hundred differentially expressed proteins were identified in HIV-infected cells by mass spectrometry and each protein was scrutinized for its biological functions by using various bioinformatics programs. Herein, we report 18 HIV-modulated proteins and their interaction pathways that enhance fatty acid synthesis, increase low density lipoproteins (triglycerides), dysregulate lipid transport, oxidize lipids, and alter cellular lipid metabolism. CONCLUSIONS: We conclude that HIV replication alone (i.e. without any influence of antiviral drugs, or other human genetic factors), can induce novel cellular enzymes and proteins that are significantly associated with biologically relevant processes involved in lipid synthesis, transport and metabolism (p = <0.0002-0.01). Translational and clinical studies on the newly discovered proteins may now shed light on how some of these proteins may be useful for early diagnosis of individuals who might be at high risk for developing lipid-related disorders. The target proteins could then be used for future studies in the development of inhibitors for preventing lipid-metabolic anomalies. This is the first direct evidence that HIV-modulates production of proteins that are significantly involved in disrupting the normal lipid-metabolic pathways.

Proteomics of canine lymphoma identifies potential cancer-specific protein markers.

PURPOSE: Early diagnosis of cancer is crucial for the success of treatment of the disease, and there is a need for markers whose differential expression between disease and normal tissue could be used as a diagnostic tool. Spontaneously occurring malignancies in pets provide a logical tool for translational research for human oncology. Lymphoma, one of the most common neoplasms in dogs, is similar to human non-Hodgkin's lymphoma and could serve as an experimental model system. EXPERIMENTAL DESIGN: Thirteen lymph nodes from normal dogs and 11 lymph nodes from dogs with B-cell lymphoma were subjected to proteomic analysis using two-dimensional PAGE separation and matrix-assisted laser desorption/ionization time-of-flight analysis. RESULTS: A total of 93 differentially expressed spots was subjected to matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry analysis, and several proteins that showed differential expression were identified. Of these, prolidase (proline dipeptidase), triosephosphate isomerase, and glutathione S-transferase were down-regulated in lymphoma samples, whereas macrophage capping protein was up-regulated in the lymphoma samples. CONCLUSIONS: These proteins represent potential markers for the diagnosis of lymphoma and should be further investigated in human samples for validation of their utility as diagnostic markers.

Myocardial ischemia: a comparison between isoflurane and enflurane in coronary artery bypass patients.

Isoflurane may precipitate ischemia in patients with coronary artery disease, presumably via "coronary steal." We sought to examine whether myocardial ischemia is more common in patients with coronary artery disease receiving isoflurane (0.7%) than in a control group receiving enflurane (0.9%). Thirty-eight patients scheduled for coronary artery bypass surgery were randomly assigned one anesthetic and monitored for ischemia. All patients had ejection fractions of at least 45%. Extraneous causes of ischemia were controlled as much as possible: arterial blood pressure was maintained within 20% of baseline (primarily with phenylephrine), heart rate was maintained below 80 bpm, effects from endotracheal intubation were monitored, and measurements were made before incision. Electrocardiogram, transthoracic echocardiography, and coronary sinus lactate measurement were used to detect ischemia. Measurements were made after insertion of vascular catheters, after intubation, and after 20 min of breathing the inhaled anesthetic. During the awake period and after induction of anesthesia with fentanyl (25 micrograms/kg), there was no significant difference detected between the two groups in incidence of ischemia: 20% in the enflurane group and 22% in the isoflurane group (P = 0.38). After 20 min of receiving the inhaled anesthetic, the incidence of ischemia in the isoflurane group increased to 50%, whereas the incidence in the enflurane group was unchanged at 20% (P = 0.02). These results show that, even with strict control of hemodynamics, isoflurane is associated with more myocardial ischemia than is enflurane.

Cardiac risk in vascular surgery. The oral dipyridamole-thallium stress test.

The value of the oral dipyridamole-thallium stress test in identifying patients at high risk of myocardial infarction after vascular procedures has not been documented. We studied prospectively 46 patients who underwent an oral dipyridamole-thallium stress test before undergoing vascular operations. Twenty patients (43%) had a positive test result, defined by a thallium defect with reperfusion, while 26 patients had a negative test result. Myocardial infarctions were documented postoperatively in 5 (25%) of 20 of the group with positive results and 1 (4%) of 26 of the group with negative results. Three of the six myocardial infarctions were clinical; all three were in the group with positive results. No correlation was identified between dipyridamole-thallium stress test results and clinical cardiac history. A positive dipyridamole-thallium stress test result is a more sensitive predictor of postoperative myocardial infarction than ejection fraction or history of coronary artery disease. The oral dipyridamole-thallium stress test is as useful as the intravenous test in this setting.

The relationship between clinical and echocardiographic findings in mitral valve prolapse.

Incorporating prognostically related auscultatory, M-mode, 2DE and recent Doppler echocardiographic features, the following strict criteria for establishing the diagnosis of mitral valve prolapse (MVP) have been advanced: 1. auscultatory; mid-to-late systolic clicks and a late systolic murmur at the apex or mid-to-late systolic clicks at the apex which move appropriately with maneuvers that alter LV volume or late systolic murmur at the apex in young patients (coinciding that a similar murmur in elderly population is non-specific for MVP); 2. two-dimensionally "targeted" M-mode criterion: marked (greater than 3 mm) late systolic buckling posterior to C-D line (moderate 2 mm late systolic buckling or 3 mm holosystolic displacement "arouse suspicion" but do not establish MVP); 3. two-dimensional echocardiographic criteria: severe bowing of leaflet(s) on the parasternal long axis and four-chamber view (mild to moderate bowing alone are unacceptable) or left atrial coaptation point; 4. Doppler echocardiographic criteria: moderate or severe Doppler mitral regurgitation with any degree of leaflet bowing or mild Doppler mitral regurgitation with at least moderate bowing of one leaflet (mild leaflet bowing and mild mitral regurgitation can be regarded as "probable MVP"). The concept of mitral valve prolapse syndrome encompasses that which was earlier described in patients with a high prevalence of symptoms. In controlled studies, however, it has become apparent that cardiac and psychiatric symptoms can be found as frequently in normal subjects as in those with MVP. These results indicate that clinicians may have erroneously diagnosed patients with MVP because of premature acceptance that MVP is the cause of a distinctive syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

Nonselective beta-receptor blocker effect on high density lipoprotein cholesterol after chronic exercise.

High density lipoprotein (HDL) cholesterol changes were followed in 45 men with coronary heart disease who underwent 12 weeks of monitored aerobic exercise. Twenty-five patients who were taking a nonselective beta-receptor blocking drug (Group 1) did not demonstrate a significant change in HDL cholesterol after exercise (mean difference 2.8 +/- 11.5 mg/dl), whereas patients who had not received a beta-blocking drug for greater than or equal to 3 months (Group 2) showed a significant increase (mean difference 8.4 +/- 5.5 mg/dl; p less than 0.05). However, for those patients in each group who had an initial HDL cholesterol level less than 35 mg/dl before exercise, there was a significant increase in HDL cholesterol levels (mean difference 8 +/- 6.9 mg/dl [p less than 0.02] and 11 +/- 3 mg/dl [p less than 0.001] for Group 1 and Group 2, respectively) and a significant decrease in the low density lipoprotein (LDL/HDL cholesterol ratio (mean difference -1.2 +/- 1.6 [p less than 0.05] and -0.9 +/- 0.57 [p less than 0.001], respectively). Patients in both groups who started exercise with an HDL cholesterol level greater than 35 mg/dl did not show a significant change after exercise. Patients in Groups 1 and 2 achieved similar levels of exercise training after 12 weeks and were closely matched in age, medications, alcohol intake and smoking. The results indicate that among high risk patients (with an abnormally low HDL cholesterol level) exercise training can induce an augmentation of HDL cholesterol in those receiving a beta-blocking drug similar to that of patients not receiving such a drug.

Exercise performance of the high risk acute myocardial infarction patient after cardiac rehabilitation.

Sixty-five subjects with a recent acute myocardial infarction (AMI), 50 men and 15 women aged 39 to 79 years (mean 62 +/- 9), were entered into a 12-week phase II cardiac rehabilitation program. Group I subjects were those with an ejection fraction greater than 40% (mean 56) and group II subjects were those with an ejection fraction less than 40% (mean 28). Subjects were further classified into those with or without myocardial ischemia (Ia, IIa and Ib, IIb, respectively) based on a treadmill stress test before entry. Work performance during the training sessions was similar for all subgroups, although group IIb had the lowest values for work rate and time of exercise for each individual activity. Subgroup analysis, as determined by a pre- and postprogram treadmill stress test, showed there was no significant difference in time of exercise, peak oxygen consumption and change in submaximal heart rate (decrease) for groups Ia, Ib or IIa. However, group IIb had poor performance in time of exercise (delta = 2 +/- 2 minutes), peak oxygen consumption (delta = 3 +/- 5 ml/min) and submaximal heart rate (delta = 0.4 +/- 17 beats/min) compared with the 3 other subgroups. These subjects also did not demonstrate an improvement of these values in the posttraining period. Patients who have had AMI and have both significant left ventricular dysfunction and myocardial ischemia did not have an adequate training response after 12 weeks of a formal phase II cardiac rehabilitation program.(ABSTRACT TRUNCATED AT 250 WORDS)

Subclinical left ventricular abnormalities in young diabetics.

Twenty young asymptomatic diabetic patients were evaluated for left ventricular dysfunction by determining the radionuclide ejection fraction response to supine bicycle ergometry. The double product at peak exercise (28,743 +/- 3,314 vs 29,007 +/- 3,625, p greater than .05) was not significantly different between the two groups. Seven of 20 diabetics had either no change or a drop in their ejection fraction during exercise while 1 of 20 control subjects had no change in ejection fraction. There was no correlation between the FBS (r = .26) and HbA1c (r = .32) and ejection fraction change during exercise, although those diabetics with LV dysfunction tended to have a higher HbA1c level as compared to diabetics with a normal response (16.8 +/- 3.1 percent vs 12.5 +/- 3.8 percent respectively, p greater than .05). The LV systolic dysfunction in young asymptomatic diabetic subjects does not appear to correlate with the degree of acute or chronic hyperglycemia, and therefore, is not a direct function of the dynamic metabolic state of diabetes.

Isolated pulmonary valve prolapse: a sign of pulmonary hypertension.

Isolated pulmonary valve prolapse may be a sign of pulmonary hypertension. Three patients with pulmonary hypertension as a result of left ventricular failure, chronic obstructive pulmonary disease, and primary pulmonary hypertension, respectively, are described in the case reports. It is likely that the morphological change of the pulmonary valve is due to exaggeration of the normal convexity of the elastic pulmonary leaflets as a result of a high pulmonary artery diastolic pressure. This two-dimensional echocardiographic sign may prove to be a useful qualitative hallmark for pulmonary hypertension. Present methods to detect pulmonary hypertension by two-dimensional echocardiography rely on remote findings of right heart abnormalities or changes in systolic time intervals. Pulmonic valve prolapse is the first direct sign of pulmonary hypertension found on two-dimensional echocardiography.

Prophylactic anticoagulation for left ventricular thrombi after acute myocardial infarction: a prospective randomized trial.

Thirty patients with a first episode of an anterior acute myocardial infarction (AMI) without a history of cardiac disease were prospectively randomized into a prophylactic heparin-treated group (group I) and a control nonanticoagulated group (group II) within 12 hours of the onset of chest pain to determine the effectiveness of anticoagulation for preventing left ventricular (LV) thrombi. Serial two-dimensional echocardiograms were performed during the hospital stay and patients were followed clinically for systemic emboli for 1 month after discharge from the hospital. Thirty-one percent of patients in group I (4/13) and 35% of patients in group II (6/17) developed LV thrombi on two-dimensional echocardiograms. There was no statistical difference in the incidence of LV thrombi between the two groups (p greater than 0.05). Infarct size as determined by creatine phosphokinase isoenzymes (2,386 +/- 1,568 vs 2,083 +/- 1,462 IU for groups I and II, respectively; p greater than 0.05), wall motion score (12.7 +/- 5 vs 10.7 +/- 5 for groups I and II, respectively; p greater than 0.05) and wall motion index (1.8 +/- 0.6 vs 1.8 +/- 0.56 for groups I and II, respectively; p greater than 0.05) were not statistically different between the two groups of patients. One patient in both groups had an embolic event. In conclusion, prophylactic anticoagulation in high-risk AMI patients for LV thrombus development does not prevent LV thrombus formation during the acute and subacute stages of an AMI. The results also suggest that anticoagulation may not prevent systemic embolization.

Aortic valve prolapse in congenital and acquired systemic disease.

Aortic valve prolapse, an uncommon finding in subjects with aortic insufficiency, occurred in one patient with rheumatoid arthritis and one with a congenital bicuspid aortic valve, conditions in which aortic insufficiency has been commonly attributed to aortic root dilatation and incomplete aortic valve closure, respectively. Aortic valve prolapse may be more commonly reported as the cause of aortic insufficiency in these conditions now that noninvasive techniques, such as echocardiography, are available.

Two-dimensional echocardiography versus surface electrocardiography for the diagnosis of acute non-Q wave myocardial infarction.

The initial two-dimensional echocardiogram (2DE) and electrocardiogram (ECG) of 50 consecutive patients with chest pain and a possible acute non-Q wave myocardial infarction (MI) were compared to each other to determine the value of 2DE in this type of acute MI. The ECG markers for a non-Q wave MI were (1) greater than or equal to 0.15 mV ST segment depression, (2) ST segment elevations with reciprocal ST segment depression, and (3) new symmetrical deep T wave changes as compared to a recent preadmission ECG. The 2DE was considered positive for MI if akinesia, dyskinesia, or severe hypokinesia was seen in one or more left ventricular segments. The sensitivity, specificity, and predictive value of the 2DE as compared to the ECG was 66% and 52%, respectively (sensitivity); 91% and 95%, respectivity (specificity); and 91% and 94%, respectively (predictive value). Statistically, there were no differences in the proportion of patients who had a positive 2DE as compared to the proportion of patients who had a positive ECG (p greater than 0.2). The ECG and 2DE results were combined and the sensitivity increased to 76% but the specificity decreased to 86%. Myocardial infarction size was not significantly different in infarcted subjects who had a positive 2DE (395 +/- 125 IU/L) as compared to those who had a negative 2DE (727 +/- 187 IU/L, p greater than 0.1).

Contractile properties of the left ventricle with aneurysm.

Twenty-five patients with an anterior wall acute myocardial infarction (AMI) were studied by 2-dimensional echocardiography (2-D echo) 3 to 5 days after the onset of chest pain, and serially over 3 to 24 months to determine if a particular pattern of contractility may predispose to left ventricular (LV) aneurysm formation. No subject had a prior AMI. In 8 subjects LV aneurysm eventually developed (group I), usually within 2 to 4 weeks of AMI; in 17 patients LV aneurysm did not develop (group II). Percent fractional shortening of the basal and midventricular segments was significantly better in group I subjects than in group II subjects (29 +/- 2% vs 20 +/- 2%, p less than 0.01, respectively, for the basal segment, and 23 +/- 1% vs 17 +/- 2%, p less than 0.02, respectively, for the midventricular segment). Infarct size as determined by peak creatine kinase isoenzyme levels was large in both groups, and there was no statistically significant difference between their mean values (2,099 +/- 620 IU vs 1,334 +/- 249 IU for groups I and II, respectively). Severe asynergy of the infarcted myocardium was present in all group I subjects and in 9 of 17 group II subjects on the initial 2-dimensional echocardiographic study. These results indicate that LV aneurysm formation depends on a critical imbalance of myocardial forces where strong LV segments cause bulging of weakened ones.

Relationship between auscultatory events and structural abnormalities in mitral valve prolapse: a two-dimensional echocardiographic evaluation.

The purpose of this study was to examine the relationship between the valvular abnormalities and auscultatory findings of patients with mitral valve prolapse (MVP). Forty patients with typical auscultatory and two-dimensional echocardiographic (2DE) findings were studied. Eleven of 14 patients with anterior leaflet MVP (group I) had mid to late systolic clicks without murmurs of mitral regurgitation, while eight of nine patients with posterior leaflet prolapse (group II) and 13 of 17 patients with combined anterior and posterior prolapse (group III) had murmurs of mitral regurgitation. In each subgroup the mitral anulus size was greater than a control group (group I = 3.8 +/- 0.1 cm, p less than 0.025; group II = 3.9 +/- 0.1 cm, p less than 0.005; group III = 4.2 +/- 0.2 cm, p less than 0.001; and control = 3.4 +/- 0.1 cm), but the largest anulus was present in patients with combined prolapse. As demonstrated by 2DE, prolapse of a single mitral leaflet may occur in many instances of MVP. Murmurs of mitral regurgitation occur frequently when the posterior mitral leaflet alone prolapses, while isolated clicks are found with anterior mitral leaflet prolapse.

Persistent ST-segment elevation and left ventricular wall abnormalities: a 2-dimensional echocardiographic study.

Twenty-three patients with an anterior wall myocardial infarction (MI) and persistent ST-segment elevations (Group I) were examined for wall motion abnormalities using 2-dimensional (2-D) echocardiography. Twenty-two (96%) had dyskinetic wall motion of the infarcted area and 10 (43%) had a left ventricular aneurysm. Among 15 patients who had a chronic anterior wall MI without ST-segment elevation (Group II), 13 (86%) had akinesia of the infarcted segment. To document that dyskinetic wall motion caused the persistent electrocardiographic ST-segment elevations, 15 patients with an acute anterior wall MI (Group III) were followed by serial 2-D echocardiography for 2 to 24 months (mean 8). Of the 10 patients who had dyskinetic wall motion abnormalities on their initial 2-D echocardiogram, persistent ST-segment elevation developed in 9. All 5 patients with akinetic or severely hypokinetic wall motion abnormalities on their first 2-D echocardiogram did not show ST-segment elevation on late follow-up surface electrocardiograms. Infarct size as determined by peak creatine kinase levels for the former subgroup was greater than that for the latter subgroup (2243 +/- 429 vs 899 +/- 320 IU, respectively, p less than 0.01). In conclusion, persistent ST-segment elevation after an acute anterior wall MI is indicative of dyskinetic wall motion rather than aneurysm formation. Dyskinesia precedes the appearance of ST-segment elevation and is probably responsible for these changes on the surface electrocardiogram. Infarct size is larger in persons in whom dyskinetic wall motion abnormalities are likely to develop.