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Biomedical subjects

D D Miller

Publications and source records attributed to D D Miller.

At least 127 records · Page 7Linked to original sources
PubMed1995

Identification and localization of three classes of myosins in pollen tubes of Lilium longiflorum and Nicotiana alata.

The presence and localization of actin and myosin have been examined in pollen tubes of Lilium longiflorum and Nicotiana alata. Immunoblot analysis of pollen tube extracts with antibodies to actin, myosins IA and IB, myosin II, and myosin V reveals the presence of these contractile proteins. Immunofluorescence microscopy using various methods to preserve the pollen tubes; chemical fixation, rapid freeze fixation and freeze substitution (RF-FS) followed by rehydration or by embeddment in a methacrylate mixture, was performed to optimize preservation. Immunocytochemistry reaffirmed that actin is localized longitudinally in the active streaming lanes and near the cortical surface of the pollen tube. Myosin I was localized to the plasma membrane, larger organelles, the surface of the generative cell and the vegetative nucleus, whereas, myosin V was found in the vegetative cytoplasm in a punctate fashion representing smaller organelles. Myosin II subfragment 1 and light meromyosin were localized in a punctate fashion on the larger organelles throughout the vegetative cytoplasm. In addition, isolated generative cells and vegetative nuclei labeled only with the myosin I antibody. Competition studies indicated the specificity of the heterologous antibodies utilized in this study suggesting the presence of three classes of myosins in pollen. These results lead to the following hypothesis: Myosin I may move the generative cell and vegetative nucleus unidirectionally through the pollen tube to the tip, while myosin V moves the smaller organelles and myosins I and II move the larger organelles (bidirectionally) that are involved in growth.

Antibodies↗
PubMed1995

Immunohistochemical characterization of immune cell composition and cytokine receptor expression in human coronary atherectomy tissue.

BACKGROUND: Prior histologic studies have examined smooth muscle cell, macrophage and thrombus constituents of atherosclerotic coronary atherectomy specimens. Lymphocytes and mononuclear leukocytes are also detectable in atherosclerotic surgical pathology specimens utilizing immunocytochemical techniques. METHODS: In order to quantify the histological contribution of cytokine receptor-expressing immunocompetent cells to human coronary artery stenoses, 30 directional atherectomy catheter biopsy specimens (wet weight < or = 10 mg) from 16 patients were snap frozen (-70 degrees C) for quantitative immunocytochemical studies. Following computer-assisted quantification of total intimal nuclei per tissue section (mean 297 +/- 177; cell density 7 +/- 5/10(4) microns 2), monoclonal antibody cytochemistry was used to identify the percentage of these cells expressing antigenic clusters of differentiation (CD) characteristic of T-lymphocytes, B-lymphocytes and monocytes. Identification of alpha (low affinity) and beta (intermediate affinity) interleukin-2 receptors on intimal cells was accomplished using a three-step streptavidin-biotin method. RESULTS: A significant percentage of intimal cells were of lymphocytic (11 +/- 13%) or monocytic (12 +/- 14%) origin, with helper T-cells (9 +/- 12%) outnumbering both suppressor T-cells (2 +/- 4%) and B-lymphocytes (1 +/- 2%). Interleukin-2 receptors were noted on 9 +/- 12% of intimal cells, including cells with a vascular smooth muscle phenotype. CONCLUSIONS: These quantitative immunocytochemical data conclusively demonstrate that lymphocytes and monocytes account for over 20% of coronary plaque cells obtained by in-vivo atherectomy, and that helper (CD4) T-cells predominate over suppressor (CD8) T-cells and B-lymphocytes. Variable interleukin-2 receptor subtype expression occurs in mononuclear leukocytes infiltrating chronic human atheroma. By applying these techniques, the therapeutic effects of cytotoxic agents on selectively targeted cytokine receptor-expressing cells may now be evaluated in vivo in small human directional coronary atherectomy specimens.

Adult↗
PubMed1994

Preoperative clinical assessment and dipyridamole thallium-201 scintigraphy for prediction and prevention of cardiac events in patients having major noncardiovascular surgery and known or suspected coronary artery disease.

The aim of this study was to assess the relative prognostic use of clinical risk stratification and intravenous dipyridamole thallium-201 scintigraphy in patients with an intermediate to high prevalence of coronary artery disease (CAD) who have undergone major noncardiovascular surgery, and to assess the effects of medical therapy or coronary revascularization based on the result of this clinical scintigraphic screening on perioperative cardiac morbidity and mortality. Patients (n = 161) with an intermediate to high likelihood of CAD had clinical assessment and intravenous dipyridamole planar thallium-201 testing which was analyzed semiquantitatively. Cardiac events were cardiac death (n = 9), nonfatal myocardial infarction (n = 6), acute pulmonary edema (n = 6), and unstable angina (n = 4). Multiple (> or = 2) clinical risk variables predicted any cardiac event (p = 0.04). Presence of multiple (> or = 2) abnormal thallium-201 segments was the only independent predictor of cardiac death or nonfatal myocardial infarction (p < 0.001), and was the most powerful multivariate predictor of any cardiac event (p < 0.002). Patients with an abnormal dipyridamole thallium-201 scan had a higher risk of perioperative cardiac death, myocardial infarction (18% vs 2%; p < 0.001), or any perioperative cardiac event (27% vs 6%; p < 0.001) when compared with those with a normal scan. Preoperative changes in anti-ischemic therapy or coronary revascularization in 36 of 72 patients with abnormal dipyridamole thallium-201 studies reduced perioperative death or myocardial infarction from 31% to 6% (p < 0.01), and all cardiac events from 47% to 8% (p < 0.001) compared with those in patients without intervention.(ABSTRACT TRUNCATED AT 250 WORDS)

Chi-Square Distribution↗
PubMed1994

A structure-activity relationship study of benzylic modifications of 4-[1-(1-naphthyl)ethyl]-1H-imidazoles on alpha 1- and alpha 2-adrenergic receptors.

The naphthalene analog of medetomidine (1), 4-[1-(1-naphthyl)ethyl]-1H- imidazole (2), is a highly potent, selective alpha 2-adrenoceptor agonist. We have initiated a structure-activity relationship study of the replacement of the methyl group on the carbon bridge between the naphthalene and imidazole rings of 2 with a hydrogen, hydroxy, methoxy, carbonyl, or trifluoromethyl group and compared their biological activities with medetomidine 1 and the optical isomers of 2. Analogs of 2 were antagonists of alpha 2A-adrenoceptor-mediated human platelet aggregation and agonists on alpha 1- and alpha 2-adrenoceptors in guinea pig ileum. The rank order and potencies of these analogs on platelets (alpha 2A-subtype) and guinea pig ileum (alpha 1-subtype) were nearly the same, whereas racemic and S-(+)-2, desmethyl, and hydroxy analogs were potent agonists on alpha 2-adrenoceptors in guinea pig ileum. With the exception of the desmethyl analog 5, none of the other analogs were as potent as the parent drug 2 on alpha 2A- (human platelets), alpha 1- (guinea pig ileum), or alpha 2- (guinea pig ileum) adrenergic receptor systems. As with analog 2, the desmethyl- and methoxy-substituted analogs retained a greater alpha 2/alpha 1-selectivity in both functional (agonist activity) and biochemical (receptor displacement) studies. Receptor binding studies indicate that S-(+)-2 possessed greater affinity than the R-(-)-isomer on both alpha 1- and alpha 2-adrenoceptors in rat brain. In addition, R-(-)-2 did not show agonist activity in alpha 2-adrenoceptors of guinea pig ileum and was 10-fold more potent than S-(+)-2 as an antagonist of alpha 2A-adrenoceptors in human platelets. Thus, the nature of the substituent and the chirality at the carbon bridge between the naphthalene and imidazole rings play an important role in maintaining potent alpha 2-adrenoceptor activity and high alpha 2/alpha 1-selectivity within the 4-substituted imidazole class.

Adrenergic alpha-Agonists↗
PubMed1994

Synthesis and biological activities of a new set of irreversibly acting 2-(4'-isothiocyanatobenzyl)imidazoline analogs in rat thoracic aorta.

IBI [2-(4'-isothiocyanatobenzyl)imidazoline, 3] has been shown to cause slow-onset, long-lasting contractions of rat thoracic aorta through a non-alpha-adrenergic receptor (non-alpha-AR) mediated mechanism. A series of IBI-related anlogs 7-14 and 16 was prepared to determine the structural requirements for the interaction with non-alpha-AR in rat aortic strips. All IBI analogs produced concentration-dependent contractile responses on rat thoracic aorta. Whereas the actions of analogs 7, 14, and 16 were partly mediated by alpha-ARs, the stimulatory activities of the remaining IBI analogs were unaffected by phenoxybenzamine pretreatment, suggesting that a non-alpha-adrenergic mechanism is involved. We have shown that the contractile actions of IBI and analogs 10-13 were not blocked with the imidazoline/guanidinium receptive site (IGRS) ligands idazoxan, cirazoline, or clonidine. However, the calcium channel blockers nifedipine or verapamil shifted the concentration-response curve of IBI and its analogs 10-13 to the right and reduced the maximal contractile responses. The action of IBI on rat thoracic aorta was reduced by the omission of extracellular calcium in the medium. These results suggest that the stimulatory activities of IBI and analogs 10-13 are not related to the activation of alpha-AR or IGRS receptors and are likely coupled to the voltage-dependent Ca2+ channels.

Animals↗
PubMed1994

Prognostic value of dipyridamole technetium-99m sestamibi myocardial tomography in patients with stable chest pain who are unable to exercise.

Unlike dipyridamole testing with thallium-201, the ability of technetium-99m sestamibi (MIBI) myocardial imaging to evaluate risk of later cardiac events has not been established. In this study, the prognostic value of dipyridamole MIBI myocardial tomography (same-day, rest-stress protocol) was assessed in 534 patients with stable chest pain consistent with angina pectoris. During follow-up (mean 13 +/- 5 months), 58 patients (11%) had a major cardiac event--nonfatal myocardial infarction (n = 14) or cardiac death (n = 44). A history of congestive heart failure, prior myocardial infarction or diabetes mellitus, and either a reversible or fixed myocardial perfusion defect on MIBI scans were univariate and multivariate predictors of increased cardiac risk. Cardiac events occurred in 2% of patients with normal MIBI scans, compared with 15% with abnormal scans, 17% with reversible perfusion defects and 16% with fixed defects (all p < 0.01). Relative risks (univariate Cox analysis) associated with an abnormal MIBI scan, a reversible perfusion defect and a fixed defect were 8.4 (95% confidence interval [CI] 2.6 to 26.8), 1.9 (95% CI 1.1 to 3.2) and 2.4 (95% CI 1.4 to 4.3), respectively. Patients with any kind of perfusion abnormality (reversible or fixed) had a significantly lower cardiac event-free survival than those with normal scans (all p < 0.0001). It is concluded that, as with thallium-201 myocardial scintigraphy, a normal MIBI scan is associated with low cardiac risk, whereas dipyridamole-induced myocardial perfusion defects identify patients with significantly increased risk.

Aged↗
PubMed1994

Gender differences in the noninvasive evaluation and management of patients with suspected coronary artery disease.

OBJECTIVE: To determine if gender-based differences exist in the post-test management and clinical outcome of patients with clinically suspected coronary artery disease who have stress electrocardiographic or myocardial perfusion imaging evaluation. DESIGN: Retrospective cohort study. SETTING: University medical center. PATIENTS: From a cohort of 3975 middle-aged patients referred for outpatient stress testing, 840 (47% women) were evaluated noninvasively for clinically suspected coronary artery disease. MEASUREMENTS: The rates of subsequent diagnostic procedures and the incidence of subsequent coronary revascularization, myocardial infarction, or cardiac death were determined for women and men. RESULTS: Pretest cardiac risk profiles were similar, except hypertension and hypercholesterolemia were more frequent in women. Atypical angina was more common in women than in men (57.5% compared with 44.5%, respectively; P < 0.001). Rates of initial test positivity (defined as exercise-induced horizontal or downsloping ST-segment depression > or = 1.0 mm or > or = 1 reversible thallium-201 defect) were similar in women and men. Compared with men, most women with an initial positive test result had no additional coronary artery disease evaluation (62.3% compared with 38.0%; P = 0.002). Coronary revascularization procedures were done more frequently in men (4.9% [22 of 449] compared with 2.0% [8 of 391]; P = 0.03). Cardiac death or myocardial infarction occurred more often in women during 2 years of follow-up (6.9% [27 of 391] compared with 2.4% [11 of 449]; P = 0.002). CONCLUSIONS: Women with suspected coronary artery disease have fewer additional diagnostic tests than men after an initial abnormal noninvasive stress test result, even though the incidence of typical angina, cardiac risk factors, and initial diagnostic test positivity rates are similar.

Adult↗
PubMed1994

Isomeric-activity ratios of trimetoquinol enantiomers on beta-adrenergic receptor subtypes: functional and biochemical studies.

Trimetoquinol [1-(3',4',5'-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4- tetrahydroisoquinoline , TMQ] exists as two enantiomers, and the (-)-(S)-isomer is a potent beta-adrenergic receptor (beta-AR) agonist. Experiments were conducted to examine the functional and biochemical potencies of the (S)-and (R)-enantiomers of TMQ for interaction with beta-AR subtypes in tissues, membrane fractions, and cell systems. The isomeric-activity ratios (IARs) of the TMQ isomers [(S)-isomer > > (R)-isomer] for stimulation of beta 1- and beta 2-AR of guinea pig right atria and trachea were 224 and 1585, respectively; these IARs were similar to those observed on atypical beta-AR systems of rat distal colon (575), rat brown adipocytes (398), but differed from that of rat esophageal smooth muscle (2884) in the presence of pindolol. In the absence of pindolol, the potencies for the TMQ enantiomers were slightly increased; however, the IARs remained unchanged in rat distal colon, rat brown adipocytes, and rat esophageal smooth muscle. Similarly, radioligand binding studies demonstrated that the TMQ isomer beta-AR affinities were stereoselective for the (-)-(S)-isomer in membranes of guinea pig left ventricle (beta 1) and lung (beta 2) giving IARs of 115 and 389, respectively; and in E. coli expressing human beta 1- and beta 2-AR giving IARs of 661 and 724, respectively. Corresponding IARs of receptor affinities and stimulation of cAMP accumulation in Chinese hamster ovary cells expressing human beta 2-AR and rat beta 3-AR were 331 and 282, and 118 and 4678, respectively. These results indicate that the (-)-(S)-isomer of TMQ exhibits high affinity, and is a potent and highly stereoselective agonist for each beta-AR subtype, that the isomers generally fail to differentiate between the beta-AR subtypes, and that, based upon differences in IAR within beta 3-AR containing systems, subtypes of atypical beta (or beta 3)-AR may exist in adipose tissue and smooth muscle.

Adrenergic beta-Agonists↗
PubMed1994

Interaction of permanently charged metoclopramide analogs with D-2 dopamine receptors.

1. The binding of permanently charged benzamides to the D-2 dopamine receptor of striatal membranes was compared with that of tertiary amine benzamides. 2. The permanently charged benzamides were able to inhibit the binding of [3H]-spiperone to striatal membranes but were less potent than the corresponding tertiary amines. 3. Removal of sodium or decreasing the pH from 7.8 to 6.2 decreased the binding of all benzamides tested, but the permanently charged analogs were affected less by these changes than the tertiary amines. 4. These results suggest that while the binding properties of the permanently charged benzamides are similar to those of the tertiary amine benzamides, there are differences in the manner in which these compounds interact with the D-2 receptor.

Animals↗
PubMed1994

Current status of myocardial perfusion imaging after percutaneous transluminal coronary angioplasty.

Controversy exists with regard to the diagnostic accuracy and optimal technique of myocardial perfusion imaging after coronary angioplasty. Exercise treadmill testing is inexpensive, with adequate predictive value for restenosis and clinical events in patients with single-vessel coronary angioplasty with a normal rest electrocardiogram (ECG). Myocardial tomography has advantages for assessing patients with multivessel coronary angioplasty. Exercise stress imaging is generally preferable to pharmacologic stress in patients without physical limitations after angioplasty. Delayed thallium-201 imaging and reinjection protocols may be useful to reconcile whether residual ischemia exists in "fixed" perfusion defects. Appropriately timed stress myocardial perfusion imaging 2 to 4 weeks after procedurally successful coronary angioplasty can document improved cardiac functional capacity and reduced ECG and imaging evidence of myocardial ischemia. Although routine serial postangioplasty evaluations cannot be recommended, stress myocardial imaging may be valuable in subjects with defective anginal nociception or extensive myocardium at risk in the area subtended by the angioplasty vessel.

Angioplasty, Balloon, Coronary↗
PubMed1994

Effect of antipsychotic withdrawal on negative symptoms in schizophrenia.

Although it is generally accepted that antipsychotic treatment improves the negative symptoms of schizophrenia in the context of improvement of positive symptoms, exactly how and to what extent they effect "primary" negative symptoms remains controversial. Antipsychotic treatment may reduce only those negative symptoms secondary to positive or depressive symptoms, and may have minimal, if any effect, on negative symptoms that represent a primary psychopathological trait manifestation of schizophrenia. In an effort to further examine this issue, we prospectively assessed negative, positive, depressive, and extrapyramidal symptoms following the discontinuation of antipsychotic medication. Fifty-nine DSM III-R schizophrenic patients underwent a three-week drug wash as part of our neuroimaging protocols. We assessed psychopathological status and adverse effects utilizing various rating instruments (i.e., Scale for Assessment of Positive Symptoms [SAPS], Scale for Assessment of Negative Symptoms [SANS], Hamilton Rating Scale for Depression, and Simpson-Angus Extrapyramidal) at baseline and weekly during this three-week period. Negative symptoms, as measured by the SANS, worsened significantly during the three-week drug wash. Positive symptoms showed a less consistent change with symptoms of disorganization worsening and with psychotic symptoms remaining the same. The changes in negative symptoms during the drug-free period were correlated with the changes in psychosis and disorganization, but not with changes in depression or extrapyramidal side effects. We were not able to substantiate if the worsening in negative symptoms was a direct result of the worsening of positive symptoms or if they were changing simultaneously, but independent of each other.

Adult↗
PubMed1994

Pollen tube growth is coupled to the extracellular calcium ion flux and the intracellular calcium gradient: effect of BAPTA-type buffers and hypertonic media.

Lily pollen tubes possess a steep, tip-focused intracellular Ca2+ gradient and a tip-directed extracellular Ca2+ influx. Ratiometric ion imaging revealed that the gradient extends from above 3.0 microM at the apex to approximately 0.2 microM within 20 microns from the tip, while application of the Ca(2+)-specific vibrating electrode indicated that the extracellular influx measured between 1.4 and 14 pmol cm-2 sec-1. We examined the relationship between these phenomena and their role in tube growth by using different 1,2-bis(o-aminophenoxy)ethane N,N,N',N'-tetraacetic acid (BAPTA)-type buffers and hypertonic media. Injection of active BAPTA-type buffers or application of elevated levels of sucrose reversibly inhibited growth, destroyed tip zonation of organelles, and modified normal patterns of cytoplasmic streaming. Simultaneously, these treatments dissipated both the intracellular tip-focused gradient and the extracellular Ca2+ flux. Of the BAPTA-type buffers, 5,5'-dibromo-BAPTA (dissociation constant [Kd] is 1.5 microM) and 4,4'-difluoro-BAPTA (Kd of 1.7 microM) exhibited greater activity than those buffers with either a higher affinity (5,5'-dimethyl-BAPTA, Kd of 0.15 microM; BAPTA, Kd of 0.21 microM; 5,5'-difluoro-BAPTA, Kd of 0.25 microM) or lower affinity (5-methyl, 5'-nitro-BAPTA, Kd of 22 microM) for Ca2+. Our findings provide evidence that growing pollen tubes have open Ca2+ channels in their tip and that these channels become inactivated in nongrowing tubes. The studies with elevated sucrose support the view that stretching of the apical plasma membrane contributes to the maintenance of the Ca2+ signal.

Buffers↗
PubMed1994

Exercise technetium-99m sestamibi tomography for cardiac risk stratification of patients with stable chest pain.

BACKGROUND: This study was designed to evaluate the prognostic value of symptom-limited maximal exercise treadmill testing with tomographic technetium-99m sestamibi (MIBI) myocardial imaging in patients referred for evaluation of stable angina. Exercise stress thallium-201 myocardial imaging provides prognostic information in coronary artery disease subsets including patients with stable chest pain. The prognostic value of exercise technetium-99m MIBI myocardial tomography has not been established. METHODS AND RESULTS: Of 548 consecutive patients with stable angina pectoris who underwent maximal exercise treadmill stress testing in combination with a same-day "rest-stress" tomographic technetium-99m MIBI myocardial imaging protocol, 521 patients were followed for 13 +/- 5 months to determine the univariate and multivariate variables associated with cardiac events and to define their cardiac event-free survival. Ten patients were lost to follow-up (98% complete), and 17 who had coronary revascularization within 6 months of testing were excluded. Major cardiac events occurred in 24 patients (9%)--nonfatal myocardial infarction in 11 and cardiac death in 13. Univariate Cox survival analysis demonstrated significant relative risk (RR) and 95% confidence intervals (CI) for exercise ST segment depression (RR = 2.3; 95% CI, 1.0 to 5.3), an abnormal MIBI scan (RR = 13.8; 95% CI, 1.9 to 102.3), and a reversible MIBI perfusion defect (RR = 3.2; 95% CI, 1.4 to 7.5). Multivariate models demonstrated that both exercise MIBI perfusion abnormalities (RR = 11.9; 95% CI, 1.6 to 89.4) and reversible MIBI perfusion defects (RR = 2.9; 95% CI, 1.2 to 7.0) had independent predictive value. During 1 year of follow-up, cardiac events occurred in only 0.5% of patients with normal MIBI scans compared with 7% of those with abnormal MIBI scans (P < .001). One-year, cardiac event-free survival was 92% in patients with reversible MIBI perfusion defects (P < .01 versus normal), 96% in patients with fixed defects (P < .01), and 93% in patients with combined reversible and fixed MIBI myocardial perfusion abnormalities (P < .02). CONCLUSIONS: As with exercise thallium-201 myocardial imaging, exercise stress technetium-99m MIBI myocardial tomography provides significant independent information concerning the subsequent risk of serious cardiac events (death, myocardial infarction) in patients with stable angina pectoris. The identification of MIBI perfusion abnormalities, in particular, the presence of reversible MIBI defects, was associated with reduced 1-year, event-free survival. The recognized imaging and radiotracer biokinetic differences between thallium-201 and MIBI do not appear to modulate the prognostic value associated with scintigraphic evidence of ischemic myocardial jeopardy in the stable angina population.

Chest Pain↗
PubMed1994

Correlation of pharmacological 99mTc-sestamibi myocardial perfusion imaging with poststenotic coronary flow reserve in patients with angiographically intermediate coronary artery stenoses.

BACKGROUND: The physiological assessment of angiographically intermediate-severity stenoses remains problematic. Functional measurements of poststenotic intracoronary Doppler coronary flow reserve can be performed in humans but have not been correlated with hyperemic myocardial perfusion imaging or angiographic data in this patient population. METHODS AND RESULTS: Thirty-three patients undergoing diagnostic quantitative coronary angiography (QCA) for assessment of intermediate-severity coronary artery disease (mean QCA percent diameter stenosis, 56 +/- 14%) were studied. Proximal and distal poststenotic Doppler coronary flow velocities were measured (left anterior descending coronary artery, 16; right coronary artery, 10; left circumflex artery, 7 patients) before and during peak maximal hyperemia with intracoronary adenosine (8 to 12 micrograms). Intravenous pharmacological stress (adenosine, 20 patients; dipyridamole, 13 patients) 99mTc-sestamibi tomographic perfusion imaging was performed within 1 week of coronary flow-velocity studies. kappa statistics were calculated to measure the strength of correlation among coronary flow velocities, perfusion imaging data, and QCA results. QCA stenosis severity (abnormal, > or = 50% diameter stenosis) and poststenotic Doppler coronary flow reserve (ratio of abnormal distal hyperemic to basal flow, < or = 2.0) were correctly correlated in 20 of 27 patients (74%; kappa = .48). QCA stenosis severity and 99mTc-sestamibi imaging (abnormal if one or more reversible myocardial segments were present in the poststenotic zone) were correlated in 28 of 33 patients (85%; kappa = .63). 99mTc-sestamibi imaging results agreed with the basal (nonhyperemic) proximal-to-distal velocity ratio (normal, < 1.7) in 15 of 31 patients (48%; kappa = .17). The strongest correlation occurred between hyperemic distal flow-velocity ratio measurements and 99mTc-sestamibi perfusion imaging results in 24 of 27 patients (89%; kappa = .78). All 14 patients with abnormal distal hyperemic flow-velocity values had corresponding reversible 99mTc-sestamibi tomographic defects. More reversibly hypoperfused segments were present in patients with abnormal poststenotic hyperemic flow-velocity ratios (abnormal, 2.4 +/- 0.7 segments; normal, 0.6 +/- 1.0 segments; P < .05). The number of poststenotic myocardial 99mTc-sestamibi perfusion defects was correlated with the QCA percent cross-sectional area reduction (P < .02) and with minimal luminal diameter (P < .05) of intermediate-severity coronary artery stenoses. CONCLUSIONS: Two technologically diverse functional measures of stenosis severity--Doppler-derived poststenotic hyperemic intracoronary flow reserve and vasodilator stress 99mTc-sestamibi myocardial perfusion imaging--are highly (89%) correlated. The physiological assessment of coronary stenoses of angiographically intermediate severity may be improved by the use of these techniques.

Adenosine↗
PubMed1994

Clozapine-associated neutropenic enterocolitis.

Clozapine's use has been restricted to the treatment of schizophrenic patients unresponsive to conventional antipsychotics, secondary to its propensity to cause agranulocytosis. Because of this restriction, side effects associated with clozapine's use have probably not been fully elucidated. The authors describe a case of a male schizophrenic who developed clozapine-induced agranulocytosis and subsequently a neutropenic enterocolitis. Neutropenic enterocolitis related to clozapine-induced neutropenia or agranulocytosis has not previously been reported in the literature. The history of clozapine, its side effects, and the phenomenon of neutropenic enterocolitis are briefly reviewed.

Agranulocytosis↗
PubMed1994

Biochemical and pharmacological characterization of high-affinity trimetoquinol analogs on guinea pig and human beta adrenergic receptor subtypes: evidence for partial agonism.

Radioligand binding assays were used to characterize the interaction of a series of trimetoquinol [1-(3',4',5'-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoqui nol ine; TMQ] analogs with beta adrenergic receptors (beta-AR). The results indicated that TMQ analogs bound with similar affinities to guinea pig (heart, lung and skeletal muscle) and human (beta-AR in Escherichia coli) beta-1- and beta-2-AR subtypes. However, the isomers of TMQ and 8-fluoro-TMQ bound stereoselectively to beta-AR with the S-isomers having affinities at least 112- and 8-fold greater, respectively, than their corresponding R-isomers. In general, a direct relationship existed between TMQ analog binding to guinea pig beta-AR and functional activity on guinea pig right atria (beta-1) and trachea (beta-2). For selected halogenated TMQ analogs (3',5'-diiodo-TMQ, 3'-iodo-TMQ, 5,8-difluoro-TMQ and 5-iodo-TMQ) which had higher beta-AR affinities than TMQ, but were less potent beta-AR agonists than TMQ, this relationship was not seen. To explain this, the function of the TMQ analogs was analyzed at the level of the beta-AR-associated effector mechanism (i.e., G-protein and adenylyl cyclase). In Chinese hamster ovary cells expressing human beta-2-AR, TMQ and halogenated analogs bound to the receptor with high affinity (nanomolar range); however, they failed to effectively couple with beta-AR-associated G-protein and only partially activated receptor-associated adenylyl cyclase. Receptor occupancies of 0.14, 2 and 23% were required for (-)-isoproterenol, S-(-)-TMQ and 3'5'-diiodo-TMQ to produce equivalent cyclic AMP accumulations in human beta-2-AR Chinese hamster ovary cells. Thus, TMQ and halogenated TMQ derivatives bind stereoselectively to beta-AR with high affinity, and may be classified as partial beta-AR agonists.

Adrenergic beta-Agonists↗