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The volume of the mediodorsal thalamic nucleus in treated and untreated schizophrenics.

Reductions of 40% in total cell number and 25% in volume of the mediodorsal thalamic nucleus were recently reported in an unbiased neurostereological study of neuroleptic-treated schizophrenic patients. In order to investigate whether these results might be secondary to many years of treatment with neuroleptic drugs, eight brains from schizophrenics never treated with neuroleptics and eight controls were studied using the unbiased Cavalieri volume estimator. To compare left-right differences in this region, twelve neuroleptic-treated schizophrenics and eleven control cases were compared. The brains used for the left-right comparison study and five of 20 used for comparison of treated and untreated brain volumes have been used in an earlier study. The mediodorsal thalamus volume was reduced by 31% in untreated schizophrenics and by 22% in neuroleptic-treated schizophrenics. No differences were found in mean total volume of the left and right mediodorsal thalamus in brains from controls nor from schizophrenics. A major difference exists with respect to time of fixation in controls (12 years) and untreated schizophrenics (39 years) that makes shrinkage differences a possible confounding variable. The results suggest that the consistent reduction in number of neurons in the mediodorsal thalamic nucleus are not secondary to prolonged treatment with neuroleptic drugs and that asymmetry in this specific brain region is not a feature of the schizophrenia-afflicted brain.

Adult↗

Postischemic stunning can affect left ventricular ejection fraction and regional wall motion on post-stress gated sestamibi tomograms.

OBJECTIVES: This study was designed to investigate whether left ventricular ejection fraction (LVEF) calculated from post-stress single-photon emission computed tomography (SPECT) reflects the basal value for LVEF or whether post-stress LVEF is reduced in some patients with stress-induced ischemia. BACKGROUND: Automated programs are now commercially available for assessing global left ventricular (LV) function from post-stress technetium-99m sestamibi gated SPECT performed >15 min after completion of exercise. METHODS: Eighty-one sequential patients who underwent a 2-day stress/rest sestamibi imaging protocol and showed perfusion defects on the post-stress tomogram underwent gated acquisition of the second-day rest tomogram. The post-stress and rest tomographic images were read for presence, location, severity and reversibility of defects by consensus of two to three experienced observers with the aid of circumferential count displays. Defects were scored as mild, moderate or severe and as completely or partially reversible or fixed, and a summed defect severity score was calculated. Of these 81 scans, 20 showed nonreversible perfusion defects (group 3), whereas 61 showed reversible perfusion defects. Post-stress and rest LVEF was calculated from the processed gated SPECT data. From 15 additional patients who underwent rest gated SPECT studies on separate days, serial reproducibility of LVEF values calculated from the gated SPECT data was determined to be +/-5.2%. Coronary angiography was performed within 3 months of the scan without intervening events in 47 of 81 patients, including 39 of 61 with reversible perfusion defects. RESULTS: In 22 (36%) of 61 patients with reversible perfusion defects, post-stress LVEF was >5% lower than that at rest (group 2), whereas in the remaining 39 patients, post-stress LVEF was either +/-5% or greater than that at rest (group 1). Segmental chordal shortening analysis performed in group 2 studies showed that differences in chordal shortening between rest and post-stress were significantly greater in the reversible perfusion defect territories than in the nonischemic perfusion defect territories ([mean +/- SD] 0.14 +/- 0.14 vs. 0.02 +/- 0.09, respectively, p < 0.0001). There were no significant differences among groups for any of the following variables: age, gender, previous myocardial infarction and type of stress. Time to imaging and stress and scan variables were correlated with the change in LVEF by univariate analysis, and the two variables that correlated significantly were the summed defect reversibility score on the scan and a left anterior descending coronary artery location of the scan defect. Only summed defect reversibility score was significant on multivariate analysis. CONCLUSIONS: When the only gated sestamibi scan is the post-stress scan, global and regional LV function will not represent basal LV function in all patients with stress-induced ischemia.

Dipyridamole↗

Transmural gradients in myocardial gas tensions in regionally ischemic canine left ventricle.

Previous studies from this laboratory have demonstrated the usefulness of myocardial gas tensions as measured by mass spectrometry for the quantitative assessment of regional myocardial ischemia (Khuri et al., 1975a). Progressive increases in myocardial carbon dioxide tensions were noted when progressive reduction in coronary blood flow was created by means of a variable constrictor. The present study was designed to determine if changes in myocardial oxygen and carbon dioxide tension were greater in deep, compared to more superficial, myocardial layers. In eight anesthetized dogs, progressive reduction in circumflex coronary flow was associated with a progressive reduction in myocardial oxygen tension and a progressive increase in myocardial carbon dioxide tension and intramyocardial ST-segment voltage. Evidence of a transmural gradient in the severity of ischemia was present at all degrees of flow reduction. These results confirm the findings of previous metabolic studies, which demonstrated gradients in lactate and high-energy phosphates. Myocardial carbon dioxide tension, which can be monitored continuously by mass spectrometry, would appear to provide a useful means of quantitatively assessing changes in regional myocardial metabolism.

Animals↗

Unique HIV type 1 V3 region sequences derived from six different regions of brain: region-specific evolution within host-determined quasispecies.

HIV type 1 viral quasispecies were amplified by polymerase chain reaction (PCR) in the hypervariable V3 region of gp120 from six different regions of the brain (right and left frontal; right and left parietal; and right and left occipital) and from the peripheral blood mononuclear cells (PBMCs) of a patient who died of AIDS dementia complex (ADC). Cloning and sequencing of the entire V3 region suggested the presence of genetically unique sequences in different regions of the brain. In contrast, the blood-derived viral quasispecies carried homogeneous sequences that were characterized by a single octapeptide crest motif (HLGPGSAF), a motif important in viral fusion. The brain-derived viral strains showed extensive sequence heterogeneity and the presence of seven different octapeptide and four different tetrapeptide crest motifs (HIGPGRAF, RIGPGRAF, HIGPGSAI, HLGPGSAF, HIGPESAI, HLGPESAI, and YLRPGSAF). In addition, the brain-derived strains were also characterized by variable net V3 loop charge and hydrophilicity, along with distinct amino acid changes specific to different brain regions. Together, the sequence and phylogenetic analyses are unique in identifying the complexity of a viral quasispecies and its independent regional evolution within the brain compartment. Uniquely divergent viral strains were identified in the frontal regions and their presence was further supported by the presence of multinucleated giant cells (characteristic of HIV encephalopathy) predominantly in the left and right frontal regions. In summary, these analyses suggest that genetically different populations of HIV-1 may be present in different brain compartments and confirm that specific neurotropic variants may exist.

Acquired Immunodeficiency Syndrome↗

Regional myocardial blood flow in awake dogs.

The objectives of this study were to test the hypothesis in awake dogs that during control conditions endocardial vessels are maximally dilated and to determine whether variables introduced by general anesthesia and thoracotomy modify distribution of myocardial blood flow or impair capacity for augmentation of flow in response to a coronary vasodilator stimulus. Myocardial blood flow was measured in relatively small, 2-3 g, left ventricular epicardial and endocardial samples by using 7-10-mum radioisotope-labeled microspheres during control conditions and during infusion of adenosine in dosages which produced maximum increases in coronary blood flow. Measurements were made initially in awake resting animals and were repeated after pentobarbital anesthesia, thoracotomy, and pericardiotomy. Blood flow (mean+/-SEM) in the epicardium and endocardium, respectively, was 0.75+/-0.06 and 0.83+/-0.06 during control conditions and 4.98+/-0.28 and 4.49+/-0.27 cm(3)/min/g during adenosine. These data demonstrate considerable capacity for vasodilation in both myocardial layers and thus refute the hypothesis that endocardial vessels are maximally dilated during control conditions. During control conditions blood flow within epicardial and endocardial layers was essentially homogeneous around the circumference of the left ventricle. In contrast to previous studies in anesthetized animals, however, transmural gradients were present in most regions, i.e., endocardium: epicardium ratio (endo/epi) 1.06-1.16. During adenosine, circumferential epicardial flows were homogeneous; however, circumferential endocardial flows were inhomogeneous and increased less than epicardial flows, endo/epi 0.81-0.99.Anesthesia, thoracotomy, and pericardiotomy increased epicardial and endocardial flow, mean values 1.08+/-0.10 and 1.11+/-0.08 cm(3)/min/g, respectively. Transmural gradients remained in only papillary muscle regions. Adenosine increased epicardial flow comparably before and after anesthesia. Although adenosine increased endocardial flow three- to fourfold after anesthesia, the increase was considerably less than epicardial flow, i.e., endo/epi 0.63-0.78.

Adenosine↗

The grade of worsening of regional function during dobutamine stress echocardiography predicts the extent of myocardial perfusion abnormalities.

AIM: To evaluate the angiographic, myocardial perfusion, and wall motion abnormalities in patients with severe compared with mild worsening of regional function during dobutamine stress echocardiography (DSE) for evaluation of myocardial ischaemia. METHODS: 147 patients with significant coronary artery disease and new or worsening wall motion abnormalities during DSE were enrolled. Left ventricular function was evaluated using a 16 segment/4 grade score model where 1 = normal and 4 = dyskinesis. Simultaneous sestamibi SPECT myocardial perfusion imaging was performed in all patients. RESULTS: Severe worsening of regional function (an increase in wall motion score of two grades or more in >/= 1 segment) was detected in 37 patients, while 110 patients had mild worsening (an increase in wall motion score of no more than one grade in >/= 1 segment). Patients with severe worsening of regional function had more stenotic coronary arteries (2.31 (0.8) v 1.97 (0. 8) (mean (SD)) (p <0.05), a higher prevalence of left anterior descending coronary artery disease (95% v 73%) (p < 0.05), a higher resting wall motion score index (1.71 (0.42) v 1.51 (0.40) (p = 0. 01), and more stress perfusion defects (3.8 (1.5) v 2.8 (1.5) (p < 0.001) compared with patients with mild worsening. Multivariate analysis identified the number of stress perfusion defects (p < 0. 005, chi(2) = 8.8) and the number of ischaemic segments on echocardiography (p < 0.05, chi(2) = 4.3) as independent variables associated with severe worsening of regional function. CONCLUSIONS: The grade of worsening of regional function during DSE predicts the underlying extent of myocardial perfusion abnormalities. The occurrence of severe worsening of regional function is associated with variables known to predict worse prognosis in patients with coronary artery disease.

Aged↗

Early systole in the healthy kidney: variability of Doppler US waveform parameters.

PURPOSE: To determine the sampling variability of intrarenal Doppler ultrasound (US) indexes of early systole in a screened population of healthy individuals. MATERIALS AND METHODS: Doppler US measurements were obtained in the superior, middle, and inferior regions of 132 kidneys in 66 healthy, potential kidney donors. All individuals subsequently underwent angiography. Systematic measurement differences and random effects were estimated for sampling from a particular parenchymal region, from a kidney in a subject, from an individual in a population, and from a vascular territory. RESULTS: Coefficients of variations ranged from 20% to 30%. Most (55%-66%) of the observed variation was attributable to random differences between repeated measurements in the same kidney. No systematic variations attributable to kidney region, vascular territory, right versus left kidney, or subject age were found for acceleration time, acceleration, or waveform shape. Some evidence of fixed variation between kidneys and between regions was found for peak systolic velocity, but the magnitude of this variation was small. Averages of repeated measurements may decrease the probability of exceeding the normal threshold for acceleration but not for acceleration time. CONCLUSION: Measurements of Doppler parameters of the early systole have substantial intrinsic variability. Thus, caution is needed when interpreting small changes in these measurements within a kidney or between individuals.

Adult↗

The embryonic ciliated band of the sea urchin, Strongylocentrotus purpuratus derives from both oral and aboral ectoderm.

The ciliated band of the Strongylocentrotus purpuratus embryo consists of a columnar epithelium, 3-5 cells wide, which gives rise to a small number of neuroblasts. It arises late in development, as a border separating the squamous epithelial cells of the oral and aboral ectoderm. To determine the lineage origins of this structure, we performed double labeling experiments at the 2-cell stage and the 16-cell stage, which were designed to reveal clonal boundaries in the ciliated band. The ciliated band forms in a region of the ectoderm derived from descendants of the following blastomeres: No, VO, Na1u, Na2u, right and left NL1u, and right and left NL2u. In contrast to the lineage contributions of the embryonic territories established early in development, lineage origins of the ciliated band are variable. Specification of the ciliated band thus depends on intercellular interaction rather than lineage.

Animals↗

Antianginal drugs and relationship between epicardial ST segment depression and moderate regional myocardial blood flow reduction in experimental partial coronary artery occlusion.

STUDY OBJECTIVE: The aim of the study was to determine whether moderate reduction in regional myocardial blood flow is related to epicardial ST segment depression and to the changes in grade and extent induced in this variable by antianginal drugs. DESIGN: Blood flow through the anterior descending coronary artery was reduced to 25-30% of control in open chest dogs, using a cuff flow meter as a monitor, and glyceryl trinitrate, propranolol and nifedipine were infused 60 min later. Regional left ventricular blood flow was measured with 15 mu radioactive microspheres and electrocardiograms were recorded from the epicardial surface of the anterior left ventricular wall before and after administration of the drugs. EXPERIMENTAL SUBJECTS: 20 adult male greyhounds were used, weighing 19-24 kg. MEASUREMENTS AND RESULTS: Under control conditions there was a poor correlation between ST segment depression and regional flow. Neither glyceryl trinitrate nor nifedipine had any significant effect on ST segment depression in sites overlying zones with a flow range of 80-105% of normal flow. On the other hand, glyceryl trinitrate, but not nifedipine, decreased ST segment depression in sites overlying the central ischaemic zone (35-80% of control posterior wall flow). With propranolol, mean ST depression was decreased significantly in sites overlying the central ischaemic zone (35-80% of control flow), but not in sites overlying zones with flows ranging from 80-105% of normal. Propranolol reduced blood flow to all zones. CONCLUSIONS: Epicardial ST segment depression is unreliable for the quantitative exploration of the grade and extent of myocardial ischaemia.

Angina Pectoris↗

The effect of diabetes on heart rate and other determinants of myocardial oxygen demand in acute coronary syndromes.

AIMS: To compare major determinants of myocardial oxygen demand (heart rate, blood pressure and rate pressure product) in patients with and without diabetes admitted with acute coronary syndromes. METHODS: A cross-sectional study of the relation between diabetes and haemodynamic indices of myocardial oxygen demand in 2542 patients with acute coronary syndromes, of whom 1041 (41.0%) had acute myocardial infarction and 1501 (59.0%) unstable angina. RESULTS: Of the 2542 patients, 701 (27.6%) had diabetes. Major haemodynamic determinants of myocardial oxygen demand were higher in patients with than without diabetes: heart rate 80.0 +/- 20.4 vs. 75.2 +/- 19.2 beats/minute (P < 0.0001); systolic blood pressure 147.3 +/- 30.3 vs. 143.2 +/- 28.5 mmHg (P = 0.002); rate-pressure product 11533 +/- 4198 vs. 10541 +/- 3689 beats/minute x mmHg (P < 0.0001). Multiple regression analysis confirmed diabetes as a significant determinant of presenting heart rate [multiplicative coefficient (MC) 1.05; 95% confidence interval (CI) 1.03-1.07; P < 0.0001], rate pressure product (MC 1.09; CI 1.05-1.12; P < 0.0001) and systolic blood pressure, which was estimated to be 3.9 mmHg higher than in patients without diabetes (P=0.003). These effects of diabetes were independent of a range of baseline variables including acute left ventricular failure and mode of presentation (unstable angina or myocardial infarction). CONCLUSIONS: In acute coronary syndromes, heart rate and other determinants of myocardial oxygen demand are higher in patients with than without diabetes, providing a potential contributory mechanism of exaggerated regional ischaemia in this high-risk group.

Acute Disease↗

Regional entrainment of atrial fibrillation studied by high-resolution mapping in open-chest dogs.

BACKGROUND: It recently has been demonstrated that during atrial fibrillation, a short and variable excitable gap exists, allowing regional control of atrial fibrillation by local stimulation. In the present study, we visualized the process of excitation during regional entrainment of atrial fibrillation by rapid pacing. METHODS AND RESULTS: In six open-chest dogs, the excitation of the left atrial free wall was mapped using a spoon-shaped mapping electrode (248 points). Episodes of atrial fibrillation were induced by burst pacing (50 Hz, 2 seconds). During atrial fibrillation, the electrograms showed rapid irregular activity with a median cycle length of 98 +/- 16 ms (mean +/- SD, n = 6). Rapid pacing in the center of the mapping electrode at intervals slightly shorter or longer than the median atrial fibrillation interval resulted in regional capture of atrial fibrillation. The window of entrainment was 16 +/- 5 ms. Mapping of atrial fibrillation showed that the left atrium was activated by fibrillatory wavelets coming from different directions. During entrainment, a relatively large area with a diameter of about 4 cm was activated by uniform wave fronts propagating away from the site of stimulation. The area of entrainment was limited by intra-atrial conduction block and by collision with fibrillation waves. Regional control of atrial fibrillation was lost by pacing either too slowly or too rapidly. In the first case, retrograde invasion of the area of entrainment by fibrillatory waves resulted in depolarization of the pacing site prior to the stimulus. Pacing too rapidly caused acceleration of atrial fibrillation by induction of local intra-atrial reentry circuits with a revolution time shorter than the pacing interval. CONCLUSIONS: During atrial fibrillation, an area with a diameter of about 4 cm can be entrained by local pacing. The resulting reduction in fibrillating tissue mass was not sufficient to terminate atrial fibrillation. Extension of the area of entrainment was limited by intra-atrial conduction block, whereas entrainment at a too high rate resulted in acceleration of atrial fibrillation by induction of local microreentry.

Animals↗

Regional diastolic wall motion dynamics in anterior myocardial infarction: analysis and quantification with magnetic resonance imaging.

BACKGROUND: Regional variability in systolic and diastolic cardiac function occurs in most cardiac disorders. The influence of this regional functional heterogeneity on global function is not well understood and is difficult to study with the common imaging modalities. METHODS: A midventricular short axis slice of the left ventricle was obtained with ECG-triggered magnetic resonance imaging in eight infarct patients and 10 control volunteers. The variation in wall thickness and slice cavity volume during the cycle was studied using the centreline method. RESULTS: The peak filling rate was significantly decreased in the infarct group (96 versus 58 cm3/s, P < 0.005). In addition, a small contribution of other parameters, such as the time to end systole, the isovolumic relaxation time, and the duration and extent of early filling, was also shown by linear discriminant analysis. Analysis of the regional parameters demonstrated an increased asynchronicity of contraction (64 versus 37 ms, P < 0.01) as well as relaxation (88 versus 51 ms, P < 0.01) in patients with myocardial infarction. On comparison of the anterior (infarcted) and inferior (non-infarcted) parts of the left ventricle, the difference was present only in the infarct region. CONCLUSION: Magnetic resonance imaging of the heart allows evaluation of the relationship between regional differences in wall motion dynamics and global parameters of diastolic function in infarct patients.

Aged↗

Standardization of an isolated pig heart preparation with parabiotic circulation: methodological considerations.

In the present study we standardized an experimental model of parabiotic circulation of isolated pig heart. The isolated heart was perfused with arterial blood from a second animal as support and submitted to regional ischemia for 30 min, followed by total ischemia for 90 min and reperfusion for 90 min. Parameters for measurement of ventricular performance using different indices measured directly or indirectly from intraventricular pressure were defined as: maximum peak pressure, final diastolic pressure, pressure developed, first derivative of maximum pressure (dP/dt max), first derivative of minimum pressure (dP/dt min), systolic stress of the left ventricle (sigmas), and maximum elastance of the left ventricle. Isolated hearts subjected to regional and global ischemia presented significant worsening of all measured parameters. Less discriminative parameters were dP/dt max and dP/dt min. Elastance was the most sensitive parameter during the reperfusion period, demonstrating an early loss of ventricular function during reperfusion. The model proved to be stable and reproducible and permitted the study of several variables in the isolated heart, such as ischemia and reperfusion phenomena, the effects of different drugs, surgical interventions, etc. The model introduces an advantage over the classical models which use crystalloid solutions as perfusate, because parabiotic circulation mimics heart surgery with extracorporeal circulation.

Analysis of Variance↗

Combined captopril and isosorbide dinitrate during healing after myocardial infarction. Effect on ventricular remodeling, function, mass and collagen.

OBJECTIVES: We sought to compare the effects of captopril plus isosorbide dinitrate versus monotherapy on infarct collagen content and left ventricular remodeling and function during healing after myocardial infarction. BACKGROUND: Captopril or isosorbide dinitrate monotherapy can limit postinfarction dilation. Whether captopril inhibits infarct collagen content, or whether captopril plus isosorbide dinitrate might be more beneficial, is not known. METHODS: In vivo remodeling variables and function (echocardiography), hemodynamic variables, postmortem topography (planimetry) and collagen content (hydroxyproline) were measured in 48 chronically instrumented dogs that were randomized 2 days after left anterior descending coronary artery ligation to 6 weeks of therapy with captopril, isosorbide dinitrate, captopril plus isosorbide dinitrate or placebo. RESULTS: Compared with placebo, the three active therapies decreased blood pressure and left atrial pressure; limited infarct expansion, infarct thinning, noninfarct wall stretching and thickening; limited left ventricular dilation and increase in left ventricular mass; and decreased regional bulging, aneurysm frequency and left ventricular dysfunction. However, the decrease in asynergy and increase in volume ejection fraction were less with captopril or captopril plus isosorbide dinitrate than with isosorbide dinitrate. Infarct thinning and bulging at 6 weeks was also less with isosorbide dinitrate than with captopril. Although initial left ventricular asynergy, final scar sizes and noninfarct collagen content at 6 weeks were similar among the groups, collagen in the center of the infarct scar was less with captopril or captopril plus isosorbide dinitrate than with placebo or isosorbide dinitrate. CONCLUSIONS: Monotherapy with captopril or isosorbide dinitrate, or their combination, improved all remodeling variables, but isosorbide dinitrate improved function more than captopril or captopril plus isosorbide dinitrate. Inhibition of infarct collagen content by captopril suggests that benefits with captopril represent a balance between positive and negative effects, and its combination with isosorbide dinitrate might be advantageous.

Animals↗

Schizophrenic auditory hallucinations are associated with increased regional cerebral blood flow during verbal memory activation in a study using single photon emission computed tomography.

Single photon emission tomography with split-dose technetium-99m-d, l-hexamethyl-propylene amine oxime was used to measure regional cerebral blood flow (rCBF) during a memory-activation paradigm in a group of 18 medicated DSM-III-R schizophrenic patients. The relationship between clinical features of schizophrenia and rCBF patterns was examined. Increased blood flow to the left basal ganglia was revealed during activation in patients reporting hallucinations in the previous month, a finding that was not influenced by medication dose or other confounding variables. This result adds to previous functional imaging studies that have related basal ganglia abnormalities to hallucinatory phenomena and suggests that left basal ganglia hyperactivity may be relevant to an internal monitoring deficit responsible for the appearance of those symptoms in schizophrenia.

Adult↗

Transesophageal echocardiography in myocardial revascularization: I. Accuracy of intraoperative real-time interpretation.

Transesophageal echocardiography (TEE) is increasingly used intraoperatively as a monitor of ventricular function and volume. Despite its increasing use, whether data from TEE monitoring can be interpreted accurately on-line in real-time is unknown. We studied the performance of five community-based, full-time cardiac anesthesiologists during 75 surgical procedures in which biplane TEE monitoring was used. Every 10 min intraoperatively, each anesthesiologist evaluated the video cine loop display of echocardiographic images to provide a real-time visual estimate of left ventricular ejection fraction area (EFA) and left ventricular filling at the level of the short axis and to assess regional wall-motion of the short axis and transgastric longitudinal views using a predefined scoring system. The same video images were analyzed quantitatively off-line by two blinded investigators. Intraoperative real-time estimates of EFA correlated moderately with off-line quantification (r = 0.8, P = 0.0001). Of the 662 cine loops analyzed by both off-line and real-time techniques, 386 (55%) were within +/-5% of each other, 495 (75%) were within +/-10% of each other, 561 (85%) were within +/-15% of each other, and 617 (93%) were within +/-20% of each other. The overall sensitivity and specificity of real-time echocardiographic ischemia detection were both 76%. However, there was individual variation among the five anesthesiologists. Recognition of normal and severe regional wall-motion abnormality, such as akinesis, had more concordance between real-time and off-line analysis, 93% and 79%, respectively, than recognition of mild regional wall-motion abnormalities. Anesthesiologists can estimate EFA in real-time to within +/-10% of off-line values in 75% of all cases. Real-time identification of normal regional function is more accurate than identification of abnormal function, i.e., there is variability in quantifying the severity of regional dysfunction.

Data Interpretation, Statistical↗

Transcribed heteroplasmic repeated sequences in the porcine mitochondrial DNA D-loop region.

The mitochondrial D-loop region of the pig, Sus scrofa, was found to be several hundred base pairs larger than the corresponding region in cow, a related artiodactyl species, primarily because of an insertion containing the tandemly repeated sequence CGTGCGTACA. Porcine mitochondrial DNA from the tissue of a single animal exhibits a large population of length polymorphs, each member of which may have as few as 14 or as many as 29 of these repeat units. This intracellular variability may be due to the repeated and self-complementary properties of this sequence, which would favor mispairing and lead to replication slippage. The repeat domain is unusual in that symmetry properties suggest it may assume alternative conformations including cruciforms and left-handed (Z) DNA. It also appears to be the longest known, naturally occurring, alternating purine-pyrimidine sequence. In order to understand the functional significance of this heteroplasmic domain that potentially disrupts a key regulatory region in the mitochondrial genome, RNA and DNA mapping studies were conducted which located this region between the H-strand replication origin and the putative L-strand transcriptional start site. H-strand RNA analysis demonstrated that this heteroplasmic region is transcribed and, therefore, that priming for H-strand DNA replication in mitochondria is independent of the primer RNA length or secondary structure.

Animals↗

Determinants of end-systolic pressure-volume relations during acute regional ischemia in situ.

The influence of extent and location of regional ischemia, baseline left ventricular systolic function, and autonomic reflexes on in situ left ventricular end-systolic pressure-volume relations (ESPVRs) during coronary occlusion were studied in 13 open-chest dogs. Circumflex or left anterior descending arteries were randomly occluded (at proximal or distal sites) for 3 minutes in reflex-blocked (n = 6, hexamethonium/vagotomy) and unblocked (n = 7) animals. Pressure-volume data were obtained by the conductance-catheter technique, with ESPVRs determined by transient inferior vena caval occlusion. Ischemic zone size was estimated for each occlusion by radiolabeled microspheres. The relative influence of each variable on ESPVR change with ischemia was determined by multiple regression analysis. As in previous studies, regional ischemia displaced ESPVRs to the right by an amount that varied directly with ischemic bed size (y = +0.48x, r = 0.76, p less than 0.001). However, in contrast to previous data, coronary occlusion also reduced the ESPVR slope (end-systolic elastance, Ees) in the majority of cases. The extent of slope change was primarily dependent on the baseline elastance (Eesbase), such that the higher the initial elastance, the larger its subsequent reduction for any amount of ischemia (delta Ees = -0.78Eesbase, r = 0.94, p less than 0.001). Active reflexes added an offset constant to this relation (+3.15 mm Hg/ml, p less than 0.001). In addition, Ees fell slightly more with larger ischemic regions. Thus, although previous studies have reported primarily rightward parallel shifts in ESPVR with regional ischemia, the present data also demonstrate that the slope of the relation is often reduced. Greater baseline elastances typical of in situ, as opposed to isolated, ventricles probably explain the differences in apparent responses.

Animals↗