Biomedical subjects
Publications and source records attributed to K D Murray.
Contemporary cardiac surgery patients have an increased incidence of risk factors that adversely affect sternal healing. We recommend routine closure of all sternotomy incisions using six overlapping figure-of-8 wire sutures. This augmented closure is simple and effective in counteracting all forces that would delay or disrupt sternal union.
Improper intracellular regulation of the ubiquitous second messenger, calcium, has been linked to several pathological conditions. The plasma membrane calcium ATPase (PMCA) is one of the primary systems for translocating calcium from the cytosol to the extracellular milieu. As an initial assessment of the possible involvement of PMCAs in kainate (KA)-induced neurodegeneration, we have determined the effect of KA-induced seizures upon PMCA mRNA and protein. In situ hybridization was performed on tissue from adult male Sprague-Dawley rats sacrificed at various time points following i.p. injection of KA. KA altered the expression within the hippocampal subfields for mRNAs of PMCA isoforms 1 and 2. PMCA 1 and 2 mRNAs exhibited hybridization below control levels 12-48 h post-injection within CA1 and CA3. Within the dentate gyrus, PMCA 2 mRNA hybridized below control levels 4 h post-injection, but recovered to control levels by 24 h post-injection. Alterations in combined PMCA protein levels occurred at all time points examined post-injection. These observations provide evidence that KA-induced seizures alter the PMCAs at the mRNA and protein levels, suggesting a possible role for this calcium efflux system in the neuronal degeneration inherent to this paradigm.
The traditional approach of total artificial heart (TAH) and ventricular assist device (VAD) development has been the mimicking of the native heart. Nonpulsatile flow using cardiopulmonary bypass has provided evidence of short-term physiologic tolerances. The design of nonpulsatile TAHs and VADs has eliminated the need for valves, flexing diaphragms, and large ventricular volumes. However, these devices require high efficiency power sources and reliable bearing seals or electromagnetic bearings while simultaneously attempting to avoid thromboemboli. The physiologic response to nonpulsatile flow is complex and variable. When compared to a pulsatile device, a nonpulsatile TAH or VAD needs to produce increased flow and higher mean intravascular pressures to maintain normal organ function. Despite its maintaining normal organ function, nonpulsatile flow does cause alterations in biochemical functions and organ specific blood flow. The combination of bioengineering superiority and the maintenance of physiologic homeostasis has directed future TAH and VAD research towards nonpulsatile systems.
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Escherichia coli has two ppGpp synthetases, PSI and PSII, encoded by the relA and spoT genes. The spoT gene also encodes a ppGpp hydrolase. During exponential growth and under various starvation conditions, the level of ppGpp depends on the balance of ppGpp synthetic and degradative activities of spoT gene products. To find out how these two activities respond to different physiological conditions and to learn about the signals involved in these responses, rates of ppGpp synthesis and degradation were determined in an E. coli B/r delta relA strain during: (1) multiple amino acid deprivation after a nutritional shift-down from glucose amino acids to glucose minimal medium; (2) carbon source starvation after a "glucose runout"; (3) energy starvation by treatment with sodium azide. To each of these conditions, bacteria responded with a similar gradual accumulation of ppGpp, occurring over a period of 20 to 40 minutes, from the basal level of 4 and 24 pmol/OD460 in glucose amino acids and glucose minimal medium, respectively, to about 100 pmol ppGpp/OD460 unit of culture mass. After multiple amino acid deprivation and during azide treatment, the rate of ppGpp synthesis increased and the rate of ppGpp degradation decreased, but in different proportions by the two kinds of treatment. After glucose runout, both ppGpp synthesis and degradation immediately decreased, but the rate of degradation was reduced more, which caused the accumulation of ppGpp despite its reduced synthesis. ppGpp synthesis required continuous protein synthesis, but ppGpp hydrolysis and its control did not: the rate of ppGpp degradation could be instantly up or down-regulated in response to changes in exogenous amino acid or glucose levels in the absence of protein synthesis. The results suggest that PSII is unstable with an average functional lifetime of 40 seconds or less, and that its activity is generated during or shortly after spoT mRNA translation in response to the availability of amino acids. This regulation is responsible for the growth medium-dependent changes in basal levels of ppGpp. ppGpp hydrolysis is controlled, i.e. inhibited, mainly during conditions of physiological stress, such as multiple amino acid deprivation or energy deprivation. This inhibition can be correlated with an inferred accumulation of uncharged tRNA. Since previous reports have indicated that uncharged tRNA inhibits purified SpoT hydrolase in vitro, it is proposed that ppGpp hydrolase activity is, indeed, controlled by the concentration of uncharged tRNA in the cell. Finally, it was found that neither relC, transcriptional regulation of spoT, nor different translation starts of spoT mRNA are directly involved in the environmental control of SpoT hydrolase and PSII activities.
We have examined the role of metabotropic glutamate receptor activation in regulating neurotrophin messenger RNA levels in the brain with the use of the selective agonist (1S,3R)-1-aminocy-clopentane-1,3-dicarboxylic acid. Intracerebroventricular injection of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid into adult adult rats resulted in increased expression of nerve growth factor and brain-derived neurotrophic factor messenger RNA in the hippocampal and pyriform cortex and decreased levels of neurotrophin-3 messenger RNA in the hippocampal dentate gyrus granule cell layer. C-fos messenger RNA levels were also increased throughout hippocampal and cortical subfields following (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid administration. (1S,3R)-1-Aminocyclopentane-1,3-dicarboxylic acid-induced changes in messenger RNA levels occurred without behavioral seizures, yet these changes were similar in magnitude and time course to early changes in neurotrophin and c-fos messenger RNA levels observed following recurrent limbic seizures. In contrast quisqualate, a potent agonist of metabotropic as well as ionotropic kainate/alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors, was only capable of inducing increased expression of brain-derived neurotrophic factor messenger RNA at doses which produced recurrent motor seizures, and both effects were completely inhibited by the non-N-methyl-D-aspartate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. Neurotrophin messenger RNA changes induced by (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid were also partially susceptible to 6-cyano-7-nitroquinoxaline-2,3-dione antagonism, as well as the specific N-methyl-D-aspartate receptor antagonist (+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)-cyclohepten-5,10- iminedizoleipine. These results suggest that (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid-sensitive metabotropic glutamate receptors can dramatically increase the expression of neurotrophin and c-fos messenger RNAs in rat forebrain without producing significant behavioral trauma and that these influences may involve ionotropic glutamate receptors in certain brain regions.
Calcium/calmodulin-dependent protein kinase type II (CamKII) is a ubiquitous brain enzyme implicated in a wide variety of neuronal processes. Understanding CamKII has become increasingly complicated with the recent identification of multiple gene transcripts coding for separate subunits. Previous studies have shown that mRNA for the alpha subunit of CamKII can be increased by reduction of afferent input. In this study we have examined the regulation of alpha CamKII mRNA following increased activity due to seizures. Using in situ hybridization with a cRNA probe against the rat alpha CamKII sequence we found reduced levels of hybridization following limbic seizures induced by lesions of the hilus of the dentate gyrus. Hybridization was most dramatically reduced in the granule cells of the dentate gyrus and the pyramidal cells of hippocampal region CA1. There were also significant reductions in hybridization in the superficial layers of neocortex and piriform cortex. In each of these region hybridization was decreased in the molecular layers which is consistent with the reported dendritic localization of alpha CamKII mRNA. All changes in mRNA content were transient, with maximal reductions at 24 h following lesion placement and a return to control levels by 96 h. These findings demonstrate the negative regulation of alpha CamKII mRNA by seizure activity and raise the possibility that synthesis of this kinase may be regulated by normal physiological activity.
The relative levels of messenger RNA for brain-derived neurotrophic factor and the alpha subunit of calcium/calmodulin-dependent protein kinase type II were examined in hippocampal sections from Alzheimer's diseased and age matched non-diseased brains by in situ hybridization histochemistry. Consistent with previous reports in monkey and rodent, calcium/calmodulin-dependent protein kinase II messenger RNA was prevalent throughout the dentate gyrus, all the principal hippocampal subfields, and adjacent cortical regions. A distribution consistent with the dendritic localization of calcium/calmodulin-dependent protein kinase II was also observed. In contrast, brain-derived neurotrophic factor messenger RNA levels were much lower than calcium/calmodulin-dependent protein kinase II messenger RNA levels and were less widely distributed. Within the hippocampus of Alzheimer's diseased brains, levels of calcium/calmodulin-dependent protein kinase II messenger RNA were increased and levels of brain-derived neurotrophic factor messenger RNA were decreased in comparison with matched controls. These changes were consistently seen in four out of six cases processed for both messenger RNA species and ranged from 150-300% relative to non-diseased brain tissue for calcium/calmodulin-dependent protein kinase II and 20-70% for brain-derived neurotrophic factor. These results suggest that within the Alzheimer's hippocampus an altered program of gene expression is occurring leading to aberrant levels of both calcium/calmodulin-dependent protein kinase II and brain-derived neurotrophic factor messenger RNA. Previous studies of the activity-dependent regulation of these messenger RNA species suggest these results are consistent with a decrease in afferent activity within the Alzheimer's hippocampus.
Cavernous hemangiomas are the most common benign tumor of the liver. A patient presented several hours after sustaining blunt trauma to the abdomen. A CT scan of the abdomen demonstrated blood in the peritoneal space and several cavernous hemangiomas of the liver. Laparoscopy confirmed the liver lesions as the source of bleeding, although there was no active blood loss. All intraabdominal blood was aspirated and the patient made an uneventful recovery without further blood loss. Laparoscopy allowed inspection of the abdomen which revealed cessation of intraabdominal hemorrhage from the cavernous hemangiomas. He made a successful recovery without further testing or operative intervention.
We examined the effects of chronic (2 weeks) treatment with a typical neuroleptic, haloperidol (1 mg/kg, s.c.), and an atypical neuroleptic, clozapine (20 mg/kg, s.c.), on neurotensin receptor (NTR) mRNA levels by in situ hybridization histochemistry. Quantitative OD analysis showed haloperidol-induced NTR mRNA levels in the substantia nigra/ventral tegmental area (SN/VTA) 110% over control levels (significant difference from the control, p < 0.05). In contrast, the same analysis applied to the sections from clozapine-treated animals showed no significant change in NTR mRNA levels compared with matched control sections (p > 0.05). Thus, chronic treatment with haloperidol but not clozapine resulted in elevated levels of NTR mRNA within the SN/VTA. These results suggest that the high incidence of extrapyramidal side effects of typical neuroleptics could result from changes in NTR expression in the SN/VTA.
Embolism remains a significant complication of the total artificial heart (TAH). The ineffectual deairing of the TAH can allow embolization of the retained air. The standard needle aspiration of TAH air (Group A) was compared with a new protocol (Group B) that included standard needle TAH aspiration plus simultaneous pumping of the TAH against an occluded ascending aorta and main pulmonary artery with vacuum applied to a needle in the proximal aorta and pulmonary artery. There were 4 calves in each group. There was no premortem evidence of systemic or pulmonary emboli. Both groups of animals were electively terminated less than 2 weeks postoperatively Postoperative mean aortic and pulmonary artery pressures were recorded for each animal. Animals in Group B had a significant decline in pulmonary artery pressures (43 +/- 12 vs. 33 +/- 8 mm Hg) 1 h after TAH implantation when compared with Group A. All other aortic and pulmonary artery pressure differences between Groups A and B were not statistically significant within 24 h of the operation. Group A animals had a 75% incidence, and Group B animals had 100% incidence of TAH thrombus. This very small thrombus was found exclusively at the inflow valve-TAH housing interface. Evaluation of the kidneys postmortem was used to identify embolic injury. All animals in Group A had evidence of acute, hemorrhagic injury, but none of the Group B animals had similar injury. Half of the animals in each group had small, fibrotic chronic renal cortical injury, which did not develop during TAH implantation.(ABSTRACT TRUNCATED AT 250 WORDS)
Recurrent spontaneous pneumothorax often requires surgical treatment following variable periods of chest tube therapy. A limited axillary thoracotomy provides sufficient exposure to isolate or excise pulmonary blebs and perform a pleurodesis. Prompt use of this surgical approach in lieu of the initial placement of a thoracostomy tube avoids prolonged hospitalization and a significant failure rate of thoracostomy tubes to resolve this problem. This operation can also prevent recurrence, a significant problem for this pathologic process. Fourteen patients with recurrent spontaneous pneumothorax underwent an axillary thoracotomy as either primary treatment or within 72 h of thoracostomy tube placement. The average follow-up was 38 months for the initial 10 patients and 23 months for the entire group. The procedure averaged 66 min in duration. The average incision was 3.3 cm in length. There was an equal male/female ratio and right-left distribution. The patients were discharged an average of 4.2 days after surgery. There were no complications. The most recent six patients with a recurrent pneumothorax were surgically treated on the day of admission without a preoperative chest tube. The other eight patients had a thoracostomy tube for control of the pneumothorax, with surgery performed within 72 h of tube placement. A limited axillary thoracotomy corrected the underlying pathology, hastened hospital discharge, limited pain, prevented short-term recurrence, and was cosmetically acceptable. A limited axillary thoracotomy is the operation of choice when a spontaneous pneumothorax requires surgery. This surgical approach has become our primary treatment for recurrent pneumothorax, avoiding the use of a preoperative thoracostomy tube and unnecessary delay, with excellent results for the patient.
Esophageal perforation is an uncommon but serious complication of penetrating injuries to the neck and chest. A case of delayed esophageal perforation in a patient with traumatic spinal cord injury is presented. The pathophysiology, diagnosis, and treatment of this potentially fatal complication are discussed.
The purpose of this investigation was to determine whether atrial natriuretic peptide (ANP) secretory function is preserved after cardiac transplantation. Thirteen hemodynamically stable outpatients performed supine exercise on a bicycle an average of 7 months after orthotopic cardiac transplantation. Right atrial pressure increased 2.2-fold (6 +/- 1 to 13 +/- 2 mm Hg) and pulmonary artery wedge pressure 2.1-fold (11 +/- 1 to 23 +/- 7 mm Hg) with exercise in the transplant recipients. Resting venous ANP level (114 +/- 19 pg/ml) and peak exercise venous level (373 +/- 61 pg/ml) was elevated in transplant recipients (p less than 0.001) compared with control subjects (21 +/- 1 and 92 +/- 14 pg/ml, respectively. This represents a 3.3-fold (114 +/- 19 to 373 +/- 61 pg/ml) increase in the ANP level from resting to exercise in transplant recipients and a 4.4-fold (21 +/- 1 to 92 +/- 14 pg/ml) increase in control subjects. A correlation between venous ANP levels and hemodynamics (right atrial pressure) was observed r = 0.49 p = 0.01. It is concluded that ANP levels at rest are elevated after cardiac transplant, the levels correlate with the intracardiac hemodynamics, and exercise-induced augmentation of plasma levels occurs.
We have localized brain-derived neurotrophic factor (BDNF) mRNA in rat brain and examined its regulation by seizure activity. In situ hybridization of BDNF 35S-cRNA most prominently labeled neurons in hippocampal stratum pyramidale and stratum granulosum, superficial olfactory cortex, pyramidal cell layers of neocortex, amygdala, claustrum, endopiriform nucleus, anterior olfactory nucleus, and ventromedial hypothalamus. Hybridization to BDNF mRNA was markedly increased in all of these regions after lesion-induced recurrent limbic seizures and within dentate gyrus granule cells following one electrically stimulated epileptiform afterdischarge. In contrast to seizure-elicited changes in nerve growth factor (NGF) mRNA expression, increases in BDNF mRNA occur in a greater number of different neuronal populations and develop several hours more rapidly in extrahippocampal loci. These results indicate that regulation by physiological activity may be an intrinsic property of this class of neurotrophic factor but that, in the recurrent seizure paradigm, different mechanisms mediate increased expression of mRNAs for BDNF and NGF outside hippocampus.
The presence of spontaneous pneumomediastinum in otherwise healthy adults is an uncommon clinical entity. An unusual case presented in a patient with anterior spinal artery syndrome with paraplegia where progressive dysphonia was the primary presenting symptom. The clinical features, treatment and proposed pathophysiology for this condition are presented.
Platypnea-orthodeoxia is an infrequently reported clinical form of position dependent dyspnea and oxygen desaturation. There are several diverse etiologies for this syndrome. This case report of a patient with platypnea-orthodeoxia is the first known presentation of a case secondary to a patent foramen ovale and idiopathic hemidiaphragm paralysis. A major problem with this disease is the clinical recognition of its existence. Full recovery is possible with proper assessment of clinical signs and symptoms, appropriate noninvasive diagnostic tests, and corrective surgery in selective cases.
BACKGROUND: The synthetic catecholamine dobutamine increases stroke volume in normal subjects and in patients with congestive heart failure. In addition to its direct influence on myocardial contractility, dobutamine may significantly modulate vascular tone because of its alpha- and beta-adrenergic agonist activity. METHODS AND RESULTS: To test the hypothesis that such vasoactive properties significantly contribute to the improved ventricular performance noted with this agent, hemodynamic parameters were measured during stepped ascension infusion of dobutamine in a model that is insensitive to positive inotropic stimulation. Administration of dobutamine in nine calves that underwent replacement of the native right and left ventricles with pneumatically driven total artificial hearts resulted in a significant (p = 0.0001) increase in cardiac output from 7.0 +/- 1.8 to 8.2 +/- 1.8 l/min and a significant (p = 0.0001) decrease in total peripheral vascular resistance from 1,224 +/- 559 to 745 +/- 317 dyne.sec/cm5. A less marked influence was noted on the pulmonary vasculature, with pulmonary vascular resistance exhibiting a significant (p less than 0.05) decrease from its baseline value only at the peak infusion. Consistent with an increase in venous return, both left and right atrial pressures increased significantly (p less than 0.005) with dobutamine administration. CONCLUSIONS: These data demonstrate that the vasoactive properties of dobutamine significantly contribute to improved ventricular performance independent of direct myocardial stimulation. This effect appears to result in part from a direct modulation of myocardial stimulation. This effect appears to result in part from a direct modulation of arterial and venous tones rather than from a reflex response to primary changes in contractility.