Postischemic hyperglycemia worsens neurologic outcome after spinal cord ischemia

PURPOSE: The neurologic effect of induced hyperglycemia in the postischemic period was investigated with a rat aortic occlusion model. METHODS: Sprague-Dawley rats weighing 200 to 350 gm were anesthetized, intubated, and ventilated with 1% to 1.5% halothane. Temperature was continuously monitored and maintained at 37 degrees +/- 0.5 degrees C. The chest was opened, the thymus excised, and the aortic arch exposed. Snares were placed around the aorta distal to the left subclavian artery and the right and left subclavian arteries. The three vessels thus isolated were occluded for 8 minutes. With snare release and withdrawal, the rats received an intraperitoneal injection of 5% dextrose in water (2 gm/kg) or an equivalent volume of 0.9% saline solution. In a second group of rats the administration of glucose or saline solution was delayed until 30 minutes after snare release. Blood samples for blood glucose determination were obtained before operation, before occlusion, immediately after occlusion, and 15, 30, 45, 60, and 240 minutes after occlusion. A neurologic deficit score was assigned at 1, 4, 18, and 24 hours after occlusion to quantify hindlimb neurologic deficit based on 15-point scale (0 = normal, 15 = severe deficit). Sham-operated rats received the same operation and injection, but the snares were only manipulated and not made occlusive. RESULTS: The rats that were administered glucose immediately after snare release showed a statistically significant exacerbation of lower extremity neurologic deficit at 24 hours after occlusion (p < or = 0.05, Mann-Whitney U test). The sham-operated rats were normal (0 score) at 24 hours. Significant elevation of blood glucose (321 +/- 33 mg/dl) was seen in the glucose-injected rats at 15 minutes and continued for up to 4 hours after occlusion (p = 0.040 and 0.014, respectively; Student's t test). CONCLUSION: Postischemic hyperglycemia immediately after a standard spinal cord ischemic stress worsens neurologic outcome.     

Loss of myocardial protection after preconditioning correlates with the time course of glycogen recovery within the preconditioned segment

BACKGROUND: Although previous investigators have demonstrated that myocardial preconditioning reduces infarct size, the mechanisms of cardioprotection associated with preconditioning are not completely understood. METHODS AND RESULTS: To test the hypothesis that preconditioning (four 5-minute episodes of ischemia each followed by 5 minutes of reperfusion) reduces infarct size by depleting cardiac glycogen stores and attenuating the degree of intracellular acidosis during subsequent prolonged left coronary artery occlusion, preconditioned and control rats were subjected to 45 minutes of left coronary artery occlusion and 120 minutes of reflow immediately after preconditioning (groups 1P and 1C, respectively) or after 30 minutes (groups 2P+30m and 2C), 1 hour (groups 3P+60m and 3C), or 6 hours (groups 4P+360m and 4C) of nonischemic recovery after preconditioning but before prolonged ischemia. In each group, cardiectomy was performed in selected rats immediately before prolonged ischemia for cardiac glycogen assay. In selected animals, 31P magnetic resonance spectroscopy was performed to monitor intracellular pH and measure high-energy phosphate levels during ischemia and reperfusion. Group 1P rats demonstrated marked glycogen depletion after preconditioning compared with controls (0.72 +/- 0.39 [n = 9] versus 5.67 +/- 1.73 [n = 12] mg glucose/g wet wt; p < 0.001 versus group 1C) that was associated with attenuation of intracellular acidosis during ischemia, as measured by 31P magnetic resonance spectroscopy (6.8 +/- 0.3 [n = 11] versus 6.2 +/- 0.3 [n = 9] pH units; p < 0.01), and marked infarct size reduction (0.3 +/- 0.6% [n = 7] versus 38.1 +/- 11.3% [n = 7], infarct size divided by risk area; p < 0.0001). During ischemia, there were no differences in myocardial ATP or phosphocreatine levels or in any hemodynamic determinant of myocardial oxygen demand between groups 1P and 1C. In preconditioned rats that were allowed to recover before ischemia (groups 2P+30m, 3P+60m, and 4P+360m), the time course of glycogen repletion paralleled the loss of protection from ischemic injury. CONCLUSIONS: Glycogen depletion and the attenuation of intracellular acidosis during ischemia appear to be important factors in delaying irreversible injury and reducing infarct size in this animal model of myocardial preconditioning.     

Mechanism and prevention of port-site tumor recurrence after laparoscopy in a murine model

Functional activation of somatosensory cortex was studied in alpha-chloralose anesthetized rats by functional magnetic resonance imaging (fMRI), using both perfusion-weighted and T2*-weighted (blood oxygenation level dependent, BOLD) imaging. The sensitivity of functional activation was altered by ventilating animals for 3 minutes with 6% CO2. Before hypercapnic conditioning, electrical stimulation of the left forepaw at a frequency of 3 Hz led to an increase of signal intensity (relative to the unstimulated baseline condition) in the right somatosensory cortex by 6+/-2% (means+/-SD) in T2*-weighted images and by 45%+/-48% in perfusion-weighted images. After hypercapnic conditioning the signal intensity increase in perfusion-weighted images doubled to 91%+/-62% (P=0.034), whereas that of T2*-weighted images only marginally increased to 7+/-4% (not significant). This different behavior in both imaging modalities is interpreted as evidence for an increased flow response in combination with a higher oxygen extraction. Thus, the fMRI data reflect hypercapnia-induced resetting of the functional-metabolic coupling of the tissue during activation.     

The three-dimensional bone interface of an osseointegrated implant. I: A morphometric evaluation in initial healing

This study was designed to determine the effect of a potent cholecystokinin antagonist, L-364,718, on canine pancreatic endocrine function following partial pancreatectomy. Plasma glucose, insulin, and glucagon were determined over a 2-hr interval following an intravenous bolus of 0.5 g/kg glucose in a 50% solution. The following groups were established: normal animals (group A, n = 5), normal animals pretreated with 20 nmole/kg L-364,178 (group B, n = 5), partially pancreatectomized animals (group C, n = 5), and partially pancreatectomized animals pretreated with 20 nmole/kg L-364,178 (group D, n = 5). In contrast to animals with an intact pancreas, pretreatment with L-364,718 following partial pancreatectomy resulted in a significant decrease in peak insulin (group C = 132.8 +/- 13.0 microU/ml vs Group D = 90.4 +/- 16.1 microU/ml, P < 0.05) and the basal-to-peak insulin difference (group C = 111.9 +/- 11.5 microU/ml vs group D = 77.5 +/- 16.6 microU/ml, P < 0.05). Despite this, the rate of glucose utilization (K value) was significantly increased in the partially pancreatectomized animals given the antagonist (group C = -1.22 +/- 0.22%/min vs group D = -2.79 +/- 0.427%/min) and there were no significant differences in basal or peak glucose when comparing the groups given L-364,718 with the groups given placebo (group A vs B and group C vs D). Thus, the CCK antagonist L-364,718 significantly decreases peak insulin in partially pancreatectomized animals but not in nonoperative control animals. There is a paradoxical increase in the rate of glucose utilization but no effect on glucose homeostasis. The effect of this antagonist in other models of reduced islet cell reserve (i.e., pancreas transplantation) remains to be determined.     

In vivo uptake of [3H]nimodipine in focal cerebral ischemia: modulation by hyperglycemia

Cell membrane depolarization and tissue acidosis occur rapidly in severely ischemic brain. Preischemic hyperglycemia is recognized to increase ischemic tissue acidosis and the present studies were undertaken to correlate depolarization and tissue acidosis during acute focal cerebral ischemia and hyperglycemia. We used a dual-label autoradiography method to simultaneously measure the in vivo distribution of [3H]nimodipine and [14C]DMO (5,5-dimethyl-2,4-oxazolidinedione) in brain to identify regions of ischemic depolarization and measure regional net tissue pH. Regional cerebral blood flow (CBF) was measured in separate studies. Measurements were made 30 minutes after combined middle cerebral artery and ipsilateral common carotid artery occlusion in normoglycemic and hyperglycemic rats. Tissue pH in the ischemic cortex was depressed to 6.76 +/- 0.11 in normoglycemic rats (n = 12) and 6.57 +/- 0.13 in hyperglycemic rats (n = 12), with significantly greater acidosis in the hyperglycemic group (P < 0.001). In contrast the ratio of [3H]nimodipine uptake in the ischemic cortex relative to the contralateral nonischemic cortex was significantly greater in normoglycemic (1.83 +/- 0.45) than hyperglycemic (1.40 +/- 0.50) rats (P < 0.05). Within this region of ischemic cortex CBF was 31 +/- 22 mL/100 g in normoglycemic rats (n = 8) and 33 +/- 22 mL/100 g/min in hyperglycemic rats (n = 9). Cerebral blood flow did not differ between these two groups in any region. Thus hyperglycemia reduced the extent of ischemic depolarization within the cortex during the first 30 minutes of focal cerebral ischemia. This effect may be related to the increased tissue acidosis or to other factors that may lessen calcium influx and preserve cellular energy stores in the ischemic cortex of the hyperglycemic rats.     

Expression of nerve-regulated genes in muscles of mouse mutants affected by spinal muscular atrophies and muscular dystrophies

OBJECTIVE: Mature lobar transplantation will increase the pediatric donor organ pool, but it remains unknown whether such grafts will grow in a developing recipient and provide adequate long-term support. We hypothesized that a mature pulmonary lobar allograft implanted in an immature recipient would grow. METHODS: We investigated our hypothesis in a porcine orthotopic left lung transplant model using animals matched by the major histocompatibility complex to minimize the effects of chronic rejection. Twenty-three immature animals (< 12 weeks of age and < 10 kg total body weight) received either sham left thoracotomy (SH control, n = 4), left upper lobectomy to study compensatory growth (UL control, n = 4), age-matched immature whole left lung transplants (IWL TXP, n = 6), mature (donor > 1 yr in age and > 40 kg in total body weight) left lower lobe transplants (MLL TXP, n = 5), or mature left upper lobe transplants (MUL TXP, n = 4). Twelve weeks after implantation, functional residual capacity of the left lung was measured and arterial blood gas samples were obtained after the native right lung had been excluded. The graft was excised and weighed, and samples for microscopy and wet/dry ratios were collected. RESULTS: Initial and final graft weights were as follows: IWL TXP group (34.6 +/- 1.5 and 107.8 +/- 5.9 gm, p < 0.0001), MLL TXP group (72.4 +/- 6.8 and 111.4 +/- 8.7, p < 0.001), and MUL TXP group (32.8 +/- 1.3 and 92.8 +/- 7.1 gm, respectively, p < 0.004). No significant differences between groups were demonstrated when functional residual capacity, wet/dry ratios, or oxygenation were compared. Immunohistochemical staining for the nuclear antigen Ki-67 demonstrated dividing pneumocytes. CONCLUSIONS: We conclude that a mature lobar graft implanted into an immature recipient grows by pneumocyte division in this model. Mature lobar transplants can be expected to grow and provide adequate long-term function in developing recipients.     

Addition of glucagon to lipid-free total parenteral nutrition reduces production of prostaglandin E2 by stimulated splenic macrophages

Sepsis is a major complication of total parenteral nutrition (TPN). Impaired immunity has been suggested as being responsible for TPN-related sepsis, but it is unknown how the immune system is affected by TPN. We recently found that administration of lipid-free TPN resulted in an increase in prostaglandin E2 (PGE2) release by stimulated splenic macrophages. This observation suggested that TPN may impair immunity through the prominent immunosuppressive effects of PGE2. In the present study, we tested the hypothesis that addition of glucagon to TPN solution may protect against the immunosuppressive effect of TPN by modifying PGE2 secretion. Adult, male Sprague-Dawley rats (n = 18) underwent jugular vein cannulation: group 1 (n = 7) received intravenous saline and chow ad libitum; group 2 (n = 6) received TPN (80 mL/24 h); and group 3 (n = 5) received TPN (80 mL/24 h) plus glucagon (100 micrograms/24 h). After 10 days, spleens were removed and splenic macrophages were isolated and cultured for 24 h in plain M199 medium (nonstimulated) or in medium containing Escherichia coli lipopolysaccharide (5 micrograms/mL) (stimulated). PGE2 release was determined by enzyme-linked immunosorbent assay. There were no differences in PGE2 release between the groups of nonstimulated cells, but when stimulated with lipopolysaccharide, the macrophages from the TPN rats (group 2) released more PGE2 (81.68 +/- 25.99 ng/2.5 x 10(6) cells) than the control group (16.04 +/- 3.26 ng/2.5 x 10(6) cells). The release of PGE2 was normalized in the TPN animals treated with glucagon (15.71 +/- 3.33 ng/2.5 x 10(6) cells). This difference was significant, with p < .05 by Tukey's test after analysis of variance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hydroxylamine treatment increases glutathione-protein and protein-protein binding in human erythrocytes

Functional development of the rat whisker somatosensory system was studied by using the (14C) 2-deoxyglucose (2DG) metabolic mapping technique. Restrained rat pups had their left mystacial vibrissae stroked for 30 minutes and their brains harvested, sectioned, and autoradiographed from the level of the lower medulla to the frontal cortex. Subjects were tested at postnatal days (PNDs) 0-9 and 21. At birth, all subjects exhibited a significant increase of 2DG uptake in the left spinal trigeminal nuclei, the principal trigeminal sensory nucleus, and a portion of the right ventral posteromedial thalamic nucleus. The primary somatosensory cortex exhibited significant 2DG uptake contralateral to stimulation by PND 6, followed by the secondary somatosensory cortex at PND 7. The pattern of 2DG uptake in the somatosensory cortices became more intense and well defined by PND 9. Given that the somatosensory system develops in an orderly fashion from the periphery to higher brain structures, the present results show that brain structures mediating whisker sensory input are not metabolically active until projections from lower somatosensory centers are established. Neurons become responsive to whisker stimulation in the subcortical structures at birth and in the somatosensory cortex a few days later. This cortical activity follows the organization of the upper tier of thalamocortical fibers into a "barrelfield." Moreover, there is a gradual enhancement in functional activity of the vibrissa neurons at different somatosensory nuclei as rats mature. The present study elucidates the time course of functional development in the rat somatosensory system.     

Peroxynitrite: a biologically significant oxidant

A prolongation of the intracellular acidosis after myocardial ischemia can protect the myocardium against reperfusion injury. In isolated hearts, this was achieved by prolongation of the extracellular acidosis. The aim of this study was to investigate whether regional reperfusion with acidotic blood after coronary artery occlusion can reduce infarct size and improve myocardial function in vivo. Anesthetized open-chest dogs were instrumented for measurement of regional myocardial function, assessed by sonomicrometry as systolic wall thickening (sWT). Infarct size was determined by triphenyltetrazolium staining after 3 h of reperfusion. The left anterior descending coronary artery (LAD) was perfused through a bypass from the left carotid artery. The animals underwent 1 h of LAD occlusion and subsequent bypass-reperfusion with normal blood (control, n = 6) or blood equilibrated to pH = 6.8 by using 0.1 mM HCl during the first 30 min of reperfusion (HCl, n = 5). Regional collateral blood flow (RCBF) at 30-min occlusion was measured by using colored microspheres. There was no difference in recovery of sWT in the LAD-perfused area between the two groups at the end of the experiments [-2.8+/-1.2% (HCl) vs. -4.4+/-2.5% (control); mean +/- SEM; p = NS]. RCBF was comparable in both groups. Infarct size (percentage of area at risk) was reduced in the treatment group (12.8+/-2.8%) compared with the control group (26.2+/-4.8%; p < 0.05). These results indicate that reperfusion injury after coronary artery occlusion can be reduced by a prolonged local extracellular acidosis in vivo.     

Lipoic acid reduces glycemia and increases muscle GLUT4 content in streptozotocin-diabetic rats

Alpha lipoic acid (lipoate [LA]), a cofactor of alpha-ketodehydrogenase, exhibits unique antioxidant properties. Recent studies suggest a direct effect of LA on glucose metabolism in both human and experimental diabetes. This study examines the possibility that LA positively affects glucose homeostasis in streptozotocin (STZ)-induced diabetic rats by altering skeletal muscle glucose utilization. Blood glucose concentration in STZ-diabetic rats following 10 days of intraperitoneal (i.p.) injection of LA 30 mg/kg was reduced compared with that in vehicle-treated diabetic rats (495 +/- 131 v 641 +/- 125 mg/dL in fed state, P = .003, and 189 +/- 48 v 341 +/- 36 mg/dL after 12-hour fast, P = .001). No effect of LA on plasma insulin was observed. Gastrocnemius muscle crude membrane GLUT4 protein was elevated both in control and in diabetic rats treated with LA by 1.5- and 2.8-fold, respectively, without significant changes in GLUT4 mRNA levels. Gastrocnemius lactic acid was increased in diabetic rats (19.9 +/- 5.5 v 10.4 +/- 2.8 mumol/g muscle, P < .05 v nondiabetic rats), and was normal in LA-treated diabetic rats (9.1 +/- 5.0 mumol/g muscle). Insulin-stimulated 2-deoxyglucose (2 DG) uptake into isolated soleus muscle was reduced in diabetic rats compared with the control group (474 +/- 15 v 568 +/- 52 pmol/mg muscle 30 min, respectively, P = .05). LA treatment prevented this reduction, resulting in insulin-stimulated glucose uptake comparable to that of nondiabetic animals. These results suggest that daily LA treatment may reduce blood glucose concentrations in STZ-diabetic rats by enhancing muscle GLUT4 protein content and by increasing muscle glucose utilization.     

Continuous monitoring of global left ventricular ejection fraction during percutaneous transluminal coronary angioplasty

Continuous monitoring of left ventricular (LV) function during percutaneous transluminal coronary angioplasty (PTCA) was performed in 40 patients (53 +/- 2 years) with a miniature, nuclear detector system after labeling the patients' red blood cells with technetium-99m. Balloon dilation (113 seconds, range 60 to 240) induced on average a 0.12 ejection fraction (EF) unit (19%) decrease in the LVEF, which was explained by a 34% increase in end-systolic counts. Balloon dilation of the left anterior descending artery (n = 23) produced a decrease in the LVEF of 0.17 +/- 0.13 EF units compared with the decrease of 0.06 +/- 0.07 EF units in patients undergoing dilation of the left circumflex artery (n = 9) and 0.05 +/- 0.04 EF units in patients treated for a stenosis of the right coronary artery (n = 8), (p = 0.02). Balloon deflation was associated with an immediate return to pre-PTCA levels. In 10 patients with 2 identical balloon occlusions, the second occlusion led to a significantly less decrease in the LVEF (0.41 +/- 0.14 vs 0.44 +/- 0.15) and electrocardiographic ST-segment deviation (88 +/- 54 microV vs 65 +/- 42 microV) than the first. We conclude that PTCA is associated with an abrupt transient decrease in the LVEF. The effect of balloon occlusion of the left anterior descending artery is more pronounced than balloon occlusion of the left circumflex and the right coronary arteries. Neither single nor multiple balloon occlusions were associated with post-PTCA global LV dysfunction, whereas the lesser degree of LV dysfunction and electrocardiographic signs of myocardial ischemia during the second of 2 identical balloon occlusions suggests that preconditioning can be induced during PTCA.     

Therapeutic time window for the 21-aminosteroid, U-74389G, in global cerebral ischemia

A novel 21-aminosteroid (U-74389G), a new potent antioxidant, was evaluated for its protective effect on transient global cerebral ischemia. Ischemia was induced by 20 minutes of four-vessel occlusion in adult male Wistar rats. Injection of 21-aminosteroid (U-74389G, 5 mg/kg intraperitoneally injected) was repeated three times. The second injection was performed 30 minutes after the first injection, and the third injection was performed 210 minutes after that. Experimental animals were divided into five groups according to the time drug administration was initiated. Group I (n = 8) began vehicle administration 30 minutes before occlusion. Group II (n = 9) started 21-aminosteroid administration 30 minutes before occlusion. Drug administration in Group III (n = 9) began at the time of reperfusion, in Group IV (n = 8), 30 minutes after reperfusion, and in Group V (n = 6), 60 minutes after reperfusion. Animals in the control group (n = 5) underwent sham operations. One week after ischemia, the number of viable pyramidal neurons was counted in the hippocampal CA1 subfield. The results were as follows: the number of living neurons in Group I was 18.8 +/- 8.7; in Group II, was 44.7 +/- 9.5; in Group III, was 46.4 +/- 9.4; in Group IV, was 40.3 +/- 6.6; in Group V, was 10.2 +/- 2.5; and in the control group was 131 +/- 3.3. Groups II, III, and IV demonstrated significantly higher numbers of living neurons compared with Group I (P < 0.05). The present study revealed that U-74389G attenuated delayed neuronal death in global cerebral ischemia when it was administered before or soon after the ischemic episode.     

Gangliosides minimize motor disabilities and histopathological changes in cortical lesioned and transplanted rats

The effect of bovine brain gangliosides was studied in rats lesioned by partial suction of the right somatosensory cortex and also in rats implanted with a piece of fetal brain tissue in this area. In both experiments a group of animals received 30 mg/kg i.p. of gangliosides daily for a period of 7 days after surgery. In lesioned rats, the untreated group showed a lower maintenance on a tight rope test at 7 as well as at 14 days, as compared with a sham-operated group (p < 0.05). In transplanted rats ganglioside treatment prevented the increase of the probability of falls from a horizontal bar at days 7 and 14 post-operations and the probability of slips on a vertical bar at day 7 (p < 0.05). Rats were killed at day 15 and brain coronal sections were obtained. Nuclear area and circularity were measured in a sample of cortical and grafted cells in a computer aid-image analyzer. Ganglioside protection on the normal size and shape of the nuclei in the ipsilateral cortex in lesioned as well as in transplanted rats (p < 0.01) was found. A higher nuclear area in ganglioside than in saline treated grafts was noted. Results suggest a protective action of the gangliosides against the lesion-induced motor dysfunction and secondary cortical cell degeneration.     

Estrogen-mediated neuroprotection after experimental stroke in male rats

BACKGROUND AND PURPOSE: We have previously shown that 17beta-estradiol reduces infarction volume in female rats. The present study determined whether single injection or chronic implantation of estrogen confers neuroprotection in male animals with middle cerebral artery occlusion (MCAO) and whether there is an interaction with endogenous testosterone. METHODS: Male Wistar rats were treated with 2 hours of reversible MCAO. In protocol 1, acute versus chronic estrogen administration was examined in groups receiving the following: Premarin (USP) 1 mg/kg IV, immediately before MCAO (Acute, n=13, plasma estradiol=171+/-51 pg/mL); 7 days of 25 microg (E25, n=10, 10+/-3 pg/mL) or 100 microg 17beta-estradiol (E100, n=12, 69+/-20 pg/mL) by subcutaneous implant; or saline (SAL, n=21, 3+/-1 pg/mL). Laser-Doppler flowmetry was used to monitor the ipsilateral parietal cortex throughout the ischemic period and early reperfusion. At 22 hours of reperfusion, infarction volume was determined by 0 2,3,5-triphenyltetrazolium chloride staining and image analysis. In protocol 2, rats were castrated to deplete endogenous testosterone and then treated with estradiol implants: castration only (CAST, n= 13, estradiol=5+/-2 pg/mL), sham-operated (SHAM, n= 10, 4+/-2 pg/mL), estradiol implant 25 microg (CAST+E25, n=16, 7+/-2 pg/mL) or 100 microg (CAST+E100, n=14, 77+/-14 pg/mL). RESULTS: Cortical infarct volumes were reduced in all estrogen-treated groups: Acute (21+/-4% of ipsilateral cortex), E25 (12+/-5%), and E100 (12+/-3%) relative to SAL (38+/-5%). Caudate infarction was similarly decreased: Acute (39+/-7% of ipsilateral striatum), E25 (25+/-7%), and E100 (34+/-6%) relative to SAL (63+/-4%). Castration did not alter ischemic outcome; cortical and caudate infarction (percentage of respective ipsilateral regions) were 37+/-5% and 59+/-5% in CAST and 39+/-7% and 57+/-5% in SHAM, respectively. Estrogen replacement reduced infarction volume in castrated animals in cortex (19+/-4% in CAST+E25 and 12+/-4% in CAST+E100) and in caudate (42+/-6% in CAST+25 and 20+/-7% in CAST + 100). Laser-Doppler flowmetry results during ischemia and reperfusion was not different among groups. CONCLUSIONS: Both acute and chronic 17beta-estradiol treatments protect male brain in experimental stroke. Testosterone availability does not alter estradiol-mediated tissue salvage after MCAO.     

In vitro hydrolysis of gliadin and casein peptides: secondary defect in coeliac disease shown by organ culture

The authors examined whether there is any correlation between the regression speed of cardiac beta (V3)-myosin heavy-chain (MHC) isozyme and duration of overload. The results showed that in the right ventricle of a 1-week overloaded group, the loaded ventricular MHC isozyme V3 (29 center dot 0 +/- 5 center dot 0%, P < 0 center dot 05) returned to the control level within 1 week after relief of overload (20 center dot 4 +/- 4 center dot 2%, P = NS), whereas in a 3 week overloaded group (32 center dot 8 +/- 5 center dot 3%, P < 0 center dot 05) it took 10 weeks (36 center dot 6 +/- 8 center dot 6%, P = NS). The left ventricle showed the same tendency as the right ventricle. In sham-operated rats, however, the changes in MHC isozyme V3 in the left ventricle were greater than those in the right ventricle. These results suggest that regression speed of the cardiac MHC isoform, changed by pressure overload, is accompanied by the duration of overload. Furthermore, the right and left ventricles may have different responsiveness to MHC isoform transitions in heart stresses.     

The function of Glu338 in the catalytic triad of the carbamoyl phosphate synthetase amidotransferase domain

The purpose of the present study was to investigate whether differences in the function of monoaminergic systems could account for the variability in attention and impulsive behaviour between rats tested in the five-choice serial reaction time task in a model of attention deficit hyperactivity disorder. The ability of a rat to sustain its attention in this task can be assessed by measuring choice accuracy (percent correct responses) to visual stimuli, whereas the percentage of premature responses indicates the level of impulsivity. Following training with the five-choice serial reaction time task, rats were decapitated and brain pieces taken for neurochemical determination. Levels of dopamine, noradrenaline, 5-hydroxytryptamine, the dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid and the 5-hydroxytryptamine metabolite, 5-hydroxyindoleacetic acid were determined in the frontal cortex, nucleus accumbens, dorsal striatum and hippocampus. Multivariate regression analysis with a stepwise method revealed that the indeces of utilization of serotonin (5-hydroxyindoleacetic acid/5-hydroxytryptamine) in the left frontal cortex and dopamine (3,4-dihydroxyphenylacetic acid/dopamine) in the right frontal cortex together accounted for 49% of the variability in attentional performance between subjects. According to the regression analysis, a negative correlation existed between the left frontal cortex 5-hydroxyindoleacetic acid/5-hydroxytryptamine and choice accuracy, and a positive correlation was observed between 3,4-dihydroxyphenylacetic acid/dopamine ratio and choice accuracy on the opposite hemisphere. Additionally, right frontal cortex serotonin utilization was found to correlate positively with the proportion of premature hole responses and this relation accounted for about 24% of the variability in this index of impulsivity between animals. These data indicate that frontal cortex dopamine and serotonin play an important role in the modulation of attention and response control.     

Effects of m-chlorophenylpiperazine on regional brain glucose utilization: a positron emission tomographic comparison of alcoholic and control subjects

m-Chlorophenylpiperazine (mCPP) is a mixed serotonin agonist/antagonist used extensively in psychiatric research. Alcoholics show blunted neuroendocrine responses to mCPP, and in some settings mCPP can induce craving for alcohol, particularly among early onset alcoholics. We used 2-[18F]-2-deoxy-D-glucose positron emission tomography to examine the effects of intravenously administered mCPP (0.08 mg/kg) on brain glucose utilization in a group of 18 male alcoholics and 12 healthy male control subjects. Differences between two sequential scans (the first followed placebo and the second followed mCPP) were evaluated statistically with a Gaussian random field-based method. Among healthy volunteers mCPP significantly increased brain glucose metabolism in the right medial and posterior orbital gyrus, the cerebellar hemispheres bilaterally, the left nucleus accumbens, the head of the caudate nucleus bilaterally, the anterior and medial-dorsal nuclei of the thalamus bilaterally, the middle frontal gyrus, the left insular cortex, the left middle temporal gyrus, and the posterior cingulate gyrus. Among alcoholic subjects mCPP significantly increased brain glucose metabolism in larger areas of the cerebellum and posterior cingulate than it did in healthy volunteers, but compared with the healthy volunteers, alcoholics showed a smaller area of mCPP-induced activation in the thalamus, almost no activation in the orbital cortices, and no activation at all in the head of the caudate nucleus or the middle frontal gyrus. These results suggest that a serotoninergic challenge activates basal ganglia circuits involving orbital and prefrontal cortices among healthy volunteers but that the response of these circuits is blunted among alcoholics.     

Glucose intolerance exaggerates left ventricular hypertrophy and dysfunction in essential hypertension

The influence of glucose intolerance, the preclinical stage of diabetes mellitus, on the progression of left ventricular hypertrophy and left ventricular dysfunction in essential hypertension, was assessed with two-dimensional M-mode echocardiography in age- and sex-matched essential hypertensive patients with (n = 28) or without (n = 44) glucose intolerance, and normotensive control subjects (n = 29). Left ventricular mass index in hypertensive patients with glucose intolerance was significantly higher than that in hypertensive patients without glucose intolerance (mean +/- SD, 115.6 +/- 28.2 v 102.1 +/- 22.1 g/m2; P < .05). Left ventricular diastolic function as reflected by peak lengthening rate was reduced in glucose-intolerant hypertensive patients than in hypertensive patients without glucose intolerance (2.68 +/- 0.71 v 3.16 +/- 0.82/sec; P < .05). End-systolic wall stress/left ventricular end-systolic volume index, an index of left ventricular contractility, was reduced more in glucose-intolerant hypertensive patients than in hypertensive patients without glucose intolerance (2.75 +/- 0.55 v 3.13 +/- 0.55 10(3) dyn.m2/cm2.mL-1; P < .01). These findings suggest that glucose intolerance accelerates progression of left ventricular hypertrophy and deteriorates left ventricular diastolic function and contractility in essential hypertension.     

Approach to density-functional ionization energy

BACKGROUND: For patients with malignant neoplasms metastatic to lung, systemic chemotherapy in doses high enough to achieve significant survival improvement is often limited by host toxicity. Isolated single-lung perfusion offers the advantage of delivering high-dose organ-specific chemotherapy while minimizing systemic toxicity. We compared the cardiac and systemic toxicities associated with intravenous administration versus isolated single-lung perfusion with doxorubicin. METHODS: Thirty-three male Fischer 344 rats weighing 275 to 300 g were randomized into three groups: normal control rats (n = 11), intravenous doxorubicin (7/mg/kg) (n = 11), and isolated left lung perfusion with 320 micrograms doxorubicin/mL (n = 11). Animals undergoing isolated single-lung perfusion were anesthetized with pentobarbital, intubated, and ventilated, and then had left thoracotomy with cannulation of the pulmonary artery and a pulmonary venotomy; pulmonary artery and vein were clamped proximally. Animals were perfused for 10 minutes at a rate of 0.5 mL/min, followed by a 5 minute rinse with buffered hespan solution. Arteriotomy and venotomy were repaired and circulation was restored. Daily weights were recorded. On day 24, cardiac output was determined in all groups by injection of radiolabeled chromium 51 microspheres. RESULTS: Animals treated with 7 mg/kg intravenous doxorubicin had a significant weight loss as compared with those treated with isolated lung perfusion (209.2 +/- 29.9 g versus 302.3 +/- 10.1 g; p < 0.01). Animals treated with isolated single-lung perfusion, after recovering from surgical stress, resumed normal growth pattern. Significant cardiac toxicities were seen in intravenously treated animals; cardiac index (27.4 +/- 6.9 versus 39.4 +/1 6.3 mL/min/100g body weight and heart weights (0.56 +/- 0.04 versus 0.88 +/- 0.09 g) were reduced in the intravenously treated group as compared with the group treated with isolated single-lung perfusion. In addition, severe hematologic toxicities are associated with intravenous doxorubicin administration. CONCLUSIONS: Intravenous administration of doxorubicin is associated with severe host toxicities, which include weight loss, decreased cardiac function, and hematologic toxicity. Isolated lung perfusion with high-dose doxorubicin is well tolerated and is associated with minimal host toxicity.     

Ischemic preconditioning attenuates postischemic coronary artery endothelial dysfunction in a model of minimally invasive direct coronary artery bypass grafting

OBJECTIVE: Unmodified reperfusion without cardioplegia in minimally invasive direct coronary artery bypass grafting procedures causes endothelial dysfunction that may predispose to polymorphonuclear neutrophil-mediated myocardial injury. This study tested the hypothesis that ischemic preconditioning in a minimally invasive direct coronary artery bypass grafting model attenuates postischemic endothelial dysfunction in coronary vessels. METHODS: In anesthetized dogs, the left anterior descending coronary artery was occluded for 30 minutes and reperfused for 3 hours without ischemic preconditioning (no-ischemic preconditioning; n = 7); in 7 dogs, the left anterior descending occlusion was preceded by 5 minutes occlusion followed by 5 minutes of reperfusion. Relaxation responses to stimulators of nitric oxide synthase were used to evaluate endothelial function in arteries from the ischemic-reperfused (left anterior descending) and nonischemic (left circumflex coronary artery) zones. RESULTS: Stimulated endothelial-dependent relaxation of epicardial left anterior descending artery to incremental concentrations of acetylcholine in the no-ischemic preconditioning animals was shifted to the right, and maximal relaxation was attenuated compared with the nonischemic left circumflex coronary artery (117% +/- 4% vs 138% +/- 5%). In contrast, acetylcholine-induced maximal relaxation was comparable in the left anterior descending artery versus left circumflex coronary artery in the ischemic preconditioning group (130% +/- 6% vs 135% +/- 5%). In 150- to 200- microm left anterior descending microvessels, 50% relaxation occurred with a lower concentration (log[M]) of acetylcholine in ischemic preconditioning versus no-ischemic preconditioning (-8.0 +/- 0.4 vs -7.0 +/- 0.1) with no group differences in smooth muscle relaxation to sodium nitroprusside, suggesting endothelial-specific damage. Adherence of fluorescent labeled polymorphonuclear neutrophils to epicardial coronary artery endothelium, used as an index of basal (unstimulated) anti-polymorphonuclear neutrophil function, was significantly attenuated by ischemic preconditioning versus no-ischemic preconditioning (293 +/- 25 polymorphonuclear neutrophils/mm2 vs 528 +/- 29 polymorphonuclear neutrophils/mm2). CONCLUSION: In this minimally invasive direct coronary artery bypass grafting model, both agonist-stimulated and basal postischemic endothelial dysfunction were attenuated by ischemic preconditioning.