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Biomedical subjects

S Kaul

Publications and source records attributed to S Kaul.

At least 91 records · Page 5Linked to original sources
PubMed2000

Metastatic pancreatic adenocarcinoma to the heart diagnosed antemortem.

Pancreatic tumors frequently metastasize widely, though it is rare to diagnose pancreatic cardiac metastases in the antemortem state. We report an unusual case of metastatic pancreatic adenocarcinoma to the right atrium. Transesophageal echocardiography showed that the tumor was attached to the superior aspect of the right atrium, prolapsing through and obstructing the tricuspid valve in diastole and retracting back into the right atrium during systole. The tumor was excised, and histologic examination confirmed the presence of moderately differentiated adenocarcinoma with a papillary architectural pattern and with desmoplastic stroma, features comparable to the original primary pancreatic neoplasm.

Adenocarcinoma↗
PubMed2000

Ordering an echocardiogram for evaluation of left ventricular function: level of expertise necessary for efficient use.

This prospective study was performed to test the hypothesis that the yield of 2-dimensional echocardiography (2DE) would be higher when it is ordered by a cardiologist than by a noncardiologist. Patients referred for transthoracic 2DE for the evaluation of left ventricular systolic function for the 11-month period between July 10, 1995, and June 10, 1996, were included in the study. Demographic, historical, and clinical findings were recorded. Whether the patient was referred by a cardiologist versus a noncardiologist was used as the predictor variable in a binary logistic regression analysis. To address the possibility that the yield of 2DE may be higher for cardiologists because the prevalence of disease in patients referred to them may be higher (selection bias), the analysis was subjected to a propensity score adjustment. Of 2176 patients referred for 2DE during the study, 1033 were referred for the evaluation of left ventricular function. The test had a positive yield in 52% of patients for cardiologists versus 31% for noncardiologists (chi(2) = 45.5, P <.0001, odds ratio 2.4 [CI = 1. 9-3.1]). This difference remained highly significant even when propensity score risk adjustment was made (chi(2) = 54.2, P <.0001, odds ratio 2.0 [CI = 1.5-2.8]). We conclude that the yield of 2DE is higher for cardiologists compared with noncardiologists and that this result was not related to differences in patient populations examined by the two groups. Thus, more efficient use of 2DE may be achieved if patients are referred to cardiologists rather than directly sent for 2DE.

Aged↗
PubMed2000

The role of constitutive NF-kappaB activity in PC-3 human prostate cancer cell invasive behavior.

The purpose of this study was to determine if increased NF-kappaB activity of highly invasive PC-3 cells contributed to their invasive behavior. Increased NF-kappaB activity has been observed in several malignant tumors and it may have an important role in tumorigenesis, progression and chemotherapy resistance. By serial selection, we obtained invasion variant PC-3 cell sublines. The PC-3 High Invasive cells invade readily through a Matrigel reconstituted basement membrane while PC-3 Low Invasive cells have low baseline invasion activity. In these studies, we discovered that NF-kappaB DNA binding activity was increased in PC-3 High Invasive cells when compared to PC-3 Low Invasive cells by electrophoretic mobility shift assay (EMSA). Gel supershift assays showed a 4-fold increase in p65 containing complexes and a 2.2-fold increase in the p50 containing complexes in the PC-3 High Invasive cells. Luciferase reporter assays showed that NF-kappaB dependent transcription activity was increased 10.2 +/- 2.5-fold in the highly invasive cells (P < 0.002). The PC-3 High Invasive cells showed a constitutive increase in phospho-IkappaB alpha and introduction of the super-repressor IkappaB alpha S32/36A inhibited NF-kappaB activity to 19.2 +/- 2.5 percent of control transfected cells (P < or = 0.001). The IkappaBa super-repressor reduced the basement membrane invasion of PC-3 High Invasive cells from 6.2 +/- 1.1 to 3.8 +/- 0.4 percent (P < 0.002) with no decrease in cell viability or proliferation. These results demonstrate that increased NF-kappaB activity contributed directly to the invasive behavior of PC-3 High Invasive prostate cancer cells.

Base Sequence↗
PubMed2000

Power doppler harmonic imaging: a feasibility study of a new technique for the assessment of myocardial perfusion.

BACKGROUND: The aim of the study was to assess the feasibility of a new technique, power Doppler harmonic imaging (PDHI), for assessing myocardial perfusion through a venous injection of microbubbles, with the use of a new ultrasound contrast agent. METHODS AND RESULTS: Fifteen patients with known coronary artery disease and a resting perfusion abnormality on Tc-99m sestamibi single-photon emission computed tomography (SPECT) underwent PDHI at rest during intravenous injections of 2 to 3 mL of Sonovue (Bracco SpA, Milan, Italy), a new second-generation ultrasound contrast agent. Myocardial perfusion was determined to be present or absent by use of a 5-segment model by 2 blinded observers for both PDHI and SPECT. Of a total of 75 possible myocardial segments, 7 (9%) were not analyzed because of obvious artifacts on PDHI. SPECT showed perfusion defects in 40 of the remaining 68 segments, whereas PDHI showed 39 defects. There was high concordance between the 2 imaging modalities for the presence (93%) as well as the location (96% for the anteroseptal region, 93% for the inferoposterior region, and 87% for the apical region) of the defects. CONCLUSIONS: These preliminary results suggest that PDHI is a feasible technique for the detection of resting myocardial perfusion defects in patients with coronary artery disease after a venous injection of a new second-generation ultrasound contrast agent.

Adult↗
PubMed2000

Quantification of mitral regurgitation in the cardiac catheterization laboratory with contrast echocardiography.

BACKGROUND: There is no method of quantifying the severity of mitral regurgitation (MR) from injection of tracer directly into the left ventricular (LV) cavity, a method commonly used in the cardiac catheterization laboratory. METHODS AND RESULTS: We used a previously validated mathematical model that derives regurgitant fraction (RF) from the relative tracer washout from the left atrial (LA) and LV cavities. Thirty-nine patients referred for diagnostic cardiac catheterization with clinical evidence of possible MR were included in the study. Five milliliters of a microbubble mixture was power-injected into the LV during simultaneously performed contrast echocardiography. Relative changes in background-subtracted video intensity were measured from the LV and LA, and the resultant model-derived RF was correlated with the severity of MR on cineangiography. The severity of MR ranged from 0 to 4+ on cineangiography with corresponding model-derived RF of 0 to 0.69 on contrast echocardiography. A close linear relation was noted between angiographic severity of MR and model-derived RF on contrast echocardiography (y = 0.1x + 0.03, r = 0.89, P <.001). Contrast echocardiography was more sensitive than cineangiography for detecting mild MR. CONCLUSIONS: We describe a new method of measuring the severity of MR in the cardiac catheterization laboratory. Apart from being quantitative, this method can be safely used during cardiac catheterization in patients in whom iodinated contrast agents may be potentially harmful.

Albumins↗
PubMed2000

Low intracellular magnesium levels promote platelet-dependent thrombosis in patients with coronary artery disease.

BACKGROUND: Although reduced intracellular levels of magnesium have been described in patients with acute myocardial infarction, its significance as a regulator of thrombosis remains unknown. METHODS AND RESULTS: To determine whether reduced intracellular levels of magnesium enhance platelet-dependent thrombosis, we evaluated 42 patients with coronary artery disease (CAD) by exposing porcine aortic media to their flowing unanticoagulated venous blood for 5 minutes by using an ex vivo perfusion (Badimon) chamber. Baseline analysis demonstrated significant associations between intracellular levels of magnesium, platelet-dependent thrombosis (P =.02), and platelet P-selectin (CD62P) expression (P <.05). Patients were divided into 2 groups: below (n = 22) and above (n = 20) the median intracellular levels of magnesium (1.12 microg/mg protein). There were no significant differences in age, body mass index, serum lipids, fibrinogen, platelet count, or serum magnesium levels between the two groups. Platelet-dependent thrombosis was significantly higher in patients with intracellular levels of magnesium below compared with above median (150 +/- 128 vs 45 +/- 28 microm(2)/mm, P <.004). Neither platelet aggregation nor CD62P expression was significantly different between the two groups. CONCLUSIONS: Platelet-dependent thrombosis was significantly increased in patients with stable CAD with low intracellular levels of magnesium, suggesting a potential role for magnesium supplementation in CAD.

Aged↗
PubMed2000

Contrast echocardiography: current and future applications.

Recent updates in the field of echocardiography have resulted in improvements in image quality, especially in those patients whose ultrasonographic (ultrasound) evaluation was previously suboptimal. Intravenous contrast agents are now available in the United States and Europe for the indication of left ventricular opacification and enhanced endocardial border delineation. The use of contrast enables acquisition of ultrasound images of improved quality. The technique is especially useful in obese patients and those with lung disease. Patients in these categories comprise approximately 10% to 20% of routine echocardiographic examinations. Stress echocardiography examinations can be even more challenging, as the image acquisition time factor is critically important for accurate detection of coronary disease. Improvements in image quality with intravenous contrast agents can facilitate image acquisition and enhance delineation of regional wall motion abnormalities at the peak level of exercise. Recent phase III clinical trial data on the use of Optison and several other agents (currently under evaluation) have revealed that for approximately half of patients, image quality substantively improves, which enables the examination to be salvaged and/or increases diagnostic accuracy. For the "difficult-to-image" patient, this added information results in (1) enhanced laboratory efficiency, (2) a reduction in downstream testing, and (3) possible improvements in patient outcome. In addition, substantial research efforts are underway to use ultrasound contrast agents for assessment of myocardial perfusion. The detection of myocardial perfusion during echocardiographic examinations will permit the simultaneous assessment of global and regional myocardial structure, function, and perfusion-all of the indicators necessary to enable the optimal noninvasive assessment of coronary artery disease. Despite the added benefit in improved efficacy of testing, few data exist regarding the long-term effectiveness of these agents. Currently under evaluation are the clinical and economic outcome implications of intravenous contrast agent use for daily clinical decision making in a variety of patient subsets. Until these data are known, this document offers a preliminary synthesis of available evidence on the value of intravenous contrast agents for use in rest and stress echocardiography. At present, it is the position of this guideline committee that intravenous contrast agents demonstrate substantial value in the difficult-to-image patient with comorbid conditions limiting an ultrasound evaluation of the heart. For such patients, the use of intravenous contrast agents should be encouraged as a means to provide added diagnostic information and to streamline early detection and treatment of underlying cardiac pathophysiology. As with all new technology, this document will require updates and revisions as additional data become available.

Contrast Media↗
PubMed2000

Quantification of the physiological relevance of a coronary stenosis using myocardial contrast echocardiography.

MCE can be used in the catheterization laboratory or in the operating room to provide rapid assessments of the functional significance of a coronary stenosis from direct arterial injections of microbubbles. In the past few years, the development of more stable microbubble contrast agents, and a better understanding of the interactions between ultrasound and microbubbles have led to the development of a truly non-invasive approach to quantify MBF using venous infusions. Furthermore, additional insights into the physiology of coronary stenosis, particularly as it affects MBV, have been obtained using MCE.

Blood Flow Velocity↗
PubMed2000

Relation between regional function and coronary blood flow reserve in multivessel coronary artery stenosis.

In the setting of chronic coronary stenoses, percent wall thickening (%WT) both at rest and during catecholamine stimulation can be abnormal despite normal resting myocardial blood flow (MBF). We hypothesized that this phenomenon is related to abnormal MBF reserve. Accordingly, 15 dogs were studied between 7 and 10 days after placement of Ameroid constrictors around the proximal coronary arteries and their major branches, at a time when collateral development had not yet occurred. %WT and MBF were measured at rest, after 0.56 mg/kg of dipyridamole, and at incremental doses of dobutamine (5-40 microgram. kg(-1). min(-1)). Resting %WT and MBF were normal in all four sham dogs. Resting transmural MBF was normal in all segments in the 11 study dogs, despite reduced (-2 SD of normal) %WT (<30%) in 40 of 82 segments. MBF reserve was reduced (<3) in segments with reduced %WT, and a close coupling was noted between resting %WT and MBF reserve. All segments showed an increase in %WT with dobutamine up to a dose of 20 microgram. kg(-1). min(-1), above which those with abnormal endocardial MBF reserve showed a "biphasic" response. It is concluded that, in the presence of chronic coronary stenoses, abnormalities in resting %WT as well as inducible reduction in %WT during pharmacological stress are related to the degree of abnormal MBF reserve.

Animals↗
PubMed2000

Growth hormone action in hypothyroid infant rats.

In neonatal rats, expression of serine protease inhibitors 2.1 and 2.3 mRNA peaks on d 2 of life and declines shortly thereafter, coinciding with levels of circulating GH. To evaluate the role of GH in this increase and to test the hypothesis that GH is active in perinatal life, we studied GH action in a model of GH deficiency. Maternal/neonatal hypothyroidism with consequent GH deficiency was induced by methimazole administration to pregnant dams. The resultant hypothyroid neonates were treated at d 2 or 7 of age with GH or saline for 1 h before exsanguination. In d-7 neonates, but not at d 2, GH administration resulted in significant serine protease inhibitors 2.1 and 2.3 mRNA induction. This treatment did not result in increased production of either GH receptor or IGF-I mRNA at either age. There was a slight GH-independent increase in GH receptor and IGF-I mRNA expression by d 7. Electromobility shift assays using hepatic nuclear extracts from these neonates and the GH response element from the serine protease inhibitor 2.1 promoter showed signal transducer and activator of transcription 5 (Stat5) binding in response to GH in extracts from d-7 rats only. Immunoblots of these extracts showed twice as much Stat5 in the nuclei of d-7 treated neonates compared with d-2 treated neonates. We conclude that there is apparent insensitivity to GH treatment in d-2 neonates that remits by d 7 and that this remission correlates with increased abundance of GH receptor and Stat5.

Animals↗
PubMed2000

Properties of the glucocorticoid modulatory element binding proteins GMEB-1 and -2: potential new modifiers of glucocorticoid receptor transactivation and members of the family of KDWK proteins.

An important component of glucocorticoid steroid induction of tyrosine aminotransferase (TAT) gene expression is the glucocorticoid modulatory element (GME), which is located at -3.6 kb of the rat TAT gene. The GME both mediates a greater sensitivity to hormone, due to a left shift in the dose-response curve of agonists, and increases the partial agonist activity of antiglucocorticoids. These properties of the GME are intimately related to the binding of a heteromeric complex of two proteins (GMEB-1 and -2). We previously cloned the rat GMEB-2 as a 67-kDa protein. We now report the cloning of the other member of the GME binding complex, the 88-kDa human GMEB-1, and various properties of both proteins. GMEB-1 and -2 each possess an intrinsic transactivation activity in mammalian one-hybrid assays, consistent with our proposed model in which they modify glucocorticoid receptor (GR)-regulated gene induction. This hypothesis is supported by interactions between GR and both GMEB-1 and -2 in mammalian two-hybrid and in pull-down assays. Furthermore, overexpression of GMEB-1 and -2, either alone or in combination, results in a reversible right shift in the dose-response curve, and decreased agonist activity of antisteroids, as expected from the squelching of other limiting factors. Additional mechanistic details that are compatible with the model of GME action are suggested by the interactions in a two-hybrid assay of both GMEBs with CREB-binding protein (CBP) and the absence of histone acetyl transferase (HAT) activity in both proteins. GMEB-1 and -2 share a sequence of 90 amino acids that is 80% identical. This region also displays homology to several other proteins containing a core sequence of KDWK. Thus, the GMEBs may be members of a new family of factors with interesting transcriptional properties.

Acetyltransferases↗
PubMed2000

Influence of immunogenicity on the pharmacokinetics of BMS-191352, a Pseudomonas exotoxin immunoconjugate, in rats and dogs.

BMS-191352 is an immunotoxin construct of modified Pseudomonas exotoxin conjugated to a fragment of the BR96 monoclonal antibody. We have investigated the potential for immunogenicity of BMS-191352 and its influence on the pharmacokinetics in rats and dogs. BMS-191352 was administered intravenously at doses of 0.75, 1.5, and 3 mg m(-2) once every two days for a total of five doses in rats, and 1.2, 2.4, and 4.8 mg m(-2) once every three days for a total of five doses in dogs. Blood samples were collected on days 1 and 9 in rats, and on days 1, 7, and 13 in dogs to monitor pharmacokinetics and anti-BMS-191352 immune response. Plasma concentrations of BMS-191352 and serum anti-BMS-191352 antibody titre were determined using ELISA assays. Pharmacokinetics were assessed using a non-compartmental method. Anti-BMS-191352 antibodies were not observed in rats within the drug administration interval. In all dogs, except one, markedly higher anti-BMS-191352 antibody titres were observed on day 13 compared with days 1 and 7, and its magnitude was independent of BMS-191352 dose. The single dose kinetics of BMS-191352 in rats and dogs were linear and the drug exposures were generally dose proportional. Mean half-life, total body clearance, and volume of distribution were 1.74 h, 3.35 mL min(-1) m(-2), and 0.27 Lm(-2) in rats, respectively, and 4.27 h, 6.28 mL min(-1) m(-2), 1.19 L m(-2) in dogs, respectively. The multiple-dose (day 9) kinetics in rats were similar to the single-dose kinetics. In dogs, the disposition of BMS-191352 on day 7 was similar to that on day 1; however, there was a precipitous reduction in the systemic drug exposure (by 5- to 110-fold) and marked increase in drug clearance on day 13. These changes in the kinetics of BMS-191352 were attributed to the generation of anti-BMS-191352 antibodies. In the one dog that did not develop anti-BMS-191352 antibodies, the pharmacokinetics were unchanged. The pharmacokinetics of BMS-191352 may be perturbed due to an immune response thus restricting the therapeutic utility of the immunotoxin.

ADP Ribose Transferases↗
PubMed2000

Interchangeability of 400-mg intravenous and oral gatifloxacin in healthy adults.

STUDY OBJECTIVE: To evaluate the interchangeability of 400-mg intravenous and oral doses of gatifloxacin. DESIGN: Randomized, open-label, crossover study. SETTING: GFI Pharmaceutical Services, Inc., Evansville, Indiana, USA. SUBJECTS: Twenty-four healthy men and women (12 of each gender), aged 18-42 years. INTERVENTIONS: Subjects received single doses of gatifloxacin 400 mg either by intravenous infusion over 1 hour or a 400-mg tablet orally with 240 ml of water, each dose separated by a 1-week washout. Plasma concentrations of gatifloxacin were determined by a validated high-performance liquid chromatography; pharmacokinetic parameters were calculated using noncompartmental methods. Distributions of pharmacokinetic parameter values were summarized by route of administration and gender. Effects of treatment on pharmacokinetic parameter values of gatifloxacin were assessed by an analysis of variance model suitable for a two-way, two-treatment, crossover design. Clinical evaluations were performed to assess drug safety and tolerability. MEASUREMENTS AND MAIN RESULTS: Intravenous and oral gatifloxacin were considered interchangeable because both routes were bioequivalent with respect to area under the curve (AUC; 90% confidence interval for the ratio of geometric means contained within 0.8-1.25). The plasma concentration-time profile after intravenous administration was similar and comparable in extent of exposure (AUC0-infinity) with that for the oral route when equal doses were administered to men and women. The absolute bioavailability of gatifloxacin after oral administration was 96%, consistent with bioequivalence of the 400-mg intravenous and oral doses. The drug was well tolerated; the frequency of adverse events was comparable after intravenous and oral administration. CONCLUSION: Intravenous and tablet formulations of gatifloxacin are bioequivalent and therefore interchangeable. This permits greater flexibility in choosing oral or parenteral therapy, with the possibility of avoiding hospitalization based on knowledge that oral administration will deliver therapeutic exposure to the drug, or abbreviating hospital stay due to ease of switching from intravenous to oral therapy.

Administration, Oral↗
PubMed2000

Assessment of resting perfusion with myocardial contrast echocardiography: theoretical and practical considerations.

BACKGROUND: The aim of this study was to perform a quantitative comparison between myocardial contrast echocardiography (MCE) and single-photon emission computed tomography (SPECT) in patients with prior myocardial infarction (MI). We also wanted to determine the optimal method for the intravenous administration of an ultrasound contrast agent in the clinical setting. METHODS AND RESULTS: Seventeen patients with resting perfusion defects in a single vascular territory on SPECT were studied. MCE was performed with intermittent harmonic imaging during continuous infusions of a second-generation ultrasound contrast agent (Sonovue, Bracco Diagnostics) in all 17 patients and after bolus injection in 8 of them. During continuous infusions, the video intensity (VI) ratio between the abnormal and normal myocardium at a pulsing interval (PI) of 8 cardiac cycles correlated well with the activity ratio between these segments on SPECT (r = 0.73, P <.01). When information regarding microbubble velocity (MV) denoted as change in VI with increasing PIs was added, the correlation with SPECT activity ratio improved (P <.05) significantly (r = 0.87, P <.0001). Higher microbubble doses resulted in higher VI during continuous infusions with good myocardial opacification and no far-field attenuation until the highest dose was reached. With bolus injections, the VI ratio between the abnormal and normal myocardium at PI of 1 and 5 cardiac cycles showed a modest correlation (r = 0.46 and r = 0.48, respectively, P <.05) with activity ratios between these regions on SPECT. When a dose of microbubbles administered as a bolus produced adequate myocardial opacification, it invariably resulted in far-field attenuation. CONCLUSIONS: In patients with prior MI, quantitative assessment of resting perfusion defects on MCE correlates well with regional activity on SPECT. Continuous infusions offer an advantage over bolus injections because they can provide an assessment of both relative VI and MV. Adjustment of the microbubble infusion rate produces adequate myocardial opacification without attenuation.

Coronary Circulation↗
PubMed2000

Efficient utilization of echocardiography for the assessment of left ventricular systolic function.

BACKGROUND: We hypothesized that patients could be selected for echocardiographic evaluation of left ventricular (LV) systolic function on the basis of historic, clinical, radiographic, and electrocardiographic criteria. METHODS AND RESULTS: We prospectively evaluated 300 consecutive inpatients referred for the echocardiographic assessment of LV function, of whom 124 (41%) had LV systolic dysfunction (LVSD) (LV ejection fraction <0.45). Among the historic variables, male sex was the only predictor of LVSD, whereas of the abnormal physical and radiographic findings, cardiomegaly on chest radiography was the only predictor. Among the electrocardiographic findings, the presence of left bundle branch block was positively correlated with the presence of LVSD, whereas a normal electrocardiogram was negatively correlated with this finding. Only 2 patients with LVSD had a normal electrocardiogram. The addition of significant predictors on physical examination and chest radiography doubled the predictive value of the historic variables for determining LVSD. The addition of electrocardiographic findings further doubled the predictive value of the model. Almost 45% of the predictive power of the final multivariate model (chi-square of 48 of the total chi-square of 108) was based on the absence of normal electrocardiogram in patients with LVSD. When chest radiographic findings were excluded from the model, the overall predictive power of the model did not change, with the normal electrocardiogram gaining greater prominence: Full 56% of the predictive power of the model (chi-square of 60 of the total chi-square of 108) resided in the ability of a normal electrocardiogram to discriminate between patients with and those without LVSD. CONCLUSIONS: Historic, chest radiographic, and electrocardiographic variables can be used to predict low likelihood of LVSD on echocardiography. In particular, when the electrocardiogram is normal, it is extremely unlikely to have LVSD. It can be argued that such patients should not be referred for echocardiography.

Aged↗