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Biomedical subjects

G F Morris

Publications and source records attributed to G F Morris.

At least 19 recordsLinked to original sources
PubMed2001

Effect of surgical cricothyrotomy on the unstable cervical spine in a cadaver model of intubation.

Cricothyrotomy is indicated for patients who require an immediate airway and in whom orotracheal or nasotracheal intubation is unsuccessful or contraindicated. Cricothyrotomy is considered safe with cervical spine (c-spine) injury; however, the amount of c-spine movement that occurs during the procedure has not been determined. In this experimental study, an established cadaver model of c-spine injury was used to quantify movement during cricothyrotomy. A complete C5--6 transection was performed by using an osteotome on 13 fresh-frozen cadavers. Standard open cricothyrotomy was performed on each cadaver, with c-spine images recorded in real time on fluoroscopy, then transferred to video and Kodachrome still images. Outcome measures included movement across the C5--6 site with regard to angulation expressed in degrees of rotation and linear measures of axial distraction and anterior-posterior (AP) displacement expressed as a proportion of C5 body width. Data were analyzed by using descriptive statistics to determine mean change from baseline in each of three planes of movement. Significance was assumed if 95% confidence intervals did not include zero. A significant amount of movement was observed with regard to AP displacement (6.3% of C5 width) and axial distraction (-4.5% of C5 width, indicating narrowing of the intervertebral space). These correspond to 1--2 mm AP displacement and less than 1 mm axial compression. No significant angular displacement was observed. In conclusion, cricothyrotomy results in a small but significant amount of movement across an unstable c-spine injury in a cadaver model. This degree of movement is less than the threshold for clinical significance.

Cadaver↗
PubMed2000

Neuromuscular blocking agents in neurointensive care.

INTRODUCTION: Intensive care treatment of patients with severe head injury is aimed at preventing secondary injury. One of the cornerstones in this treatment is sedation and ventilation. Use of Neuromuscular Blocking Agents (NBA) has gained widespread use as part of the protocol for maintaining normal intracranial pressure values, without class 1 evidence for the efficacy of the treatment. METHODS: We examined data of the use of NBA as infusion during ventilator treatment, and IntraCranial Pressure (ICP) measurements in the database from the international multicenter randomized double blind trial of the NMDA receptor antagonist Selfotel. No specific mode of sedation was recommended in the study protocol. RESULTS: Of the 427 patients enrolled in the study 326 had a full data set, 138 received NBA during their stay in the ICU. There were no statistical difference in demographic data between the two groups. During their stay in the ICU, patients who received NBA had a median of 13.5 hours with a recorded ICP above 20 mm Hg, patients who did not receive NBA had a median of 6.5 hours with ICP above 20 mm Hg (p < 0.05). CONCLUSION: Our data challenges the concept of using NBA as part of a routine sedation strategy in treatment of patients with severe head injury.

Adult↗
PubMed2000

Effects of cervical spine immobilization technique and laryngoscope blade selection on an unstable cervical spine in a cadaver model of intubation.

STUDY OBJECTIVE: Orotracheal intubation (OTI) is commonly used to establish a definitive airway in major trauma victims, with several different cervical spine immobilization techniques and laryngoscope blade types used. This experimental, randomized, crossover trial evaluated the effects of manual in-line stabilization and cervical collar immobilization and 3 different laryngoscope blades on cervical spine movement during OTI in a cadaver model of cervical spine injury. METHODS: A complete C5-C6 transection was performed by using an osteotome on 14 fresh-frozen cadavers. OTI was performed in a randomized crossover fashion by using both immobilization techniques and each of 3 laryngoscope blades: the Miller straight blade, the Macintosh curved blade, and the Corazelli-London-McCoy hinged blade. Intubations were recorded in real time on fluoroscopy and then transferred to video and color still images. Outcome measures included movement across C5-C6 with regard to angulation expressed in degrees of rotation and axial distraction and anteroposterior displacement with values expressed as a proportion of C5 body width. Cormack-Lehane visualization grades were also recorded as a secondary outcome measure. Data were analyzed by using multivariate analysis of variance to test for differences between immobilization techniques and between laryngoscope blades and to detect for interactions. Significance was assumed for P values of less than.05. RESULTS: Manual in-line stabilization resulted in significantly less movement than cervical collar immobilization during OTI with regard to anteroposterior displacement. Use of the Miller straight blade resulted in significantly less movement than each of the other 2 blades with regard to axial distraction. The Cormack-Lehane grade was significantly better with manual in-line stabilization versus cervical collar immobilization; no differences were observed between blades. CONCLUSION: Manual in-line stabilization results in less cervical subluxation and allows better vocal cord visualization during OTI in a cadaver model of cervical spine injury. The Miller laryngoscope blade allowed less axial distraction than the Macintosh or Corzelli-London-McCoy blades. The clinical significance of this degree of movement is unclear.

Cadaver↗
PubMed2000

Intracranial hypertension and cerebral perfusion pressure: influence on neurological deterioration and outcome in severe head injury. The Executive Committee of the International Selfotel Trial.

OBJECT: Recently, a renewed emphasis has been placed on managing severe head injury by elevating cerebral perfusion pressure (CPP), which is defined as the mean arterial pressure minus the intracranial pressure (ICP). Some authors have suggested that CPP is more important in influencing outcome than is intracranial hypertension, a hypothesis that this study was designed to investigate. METHODS: The authors examined the relative contribution of these two parameters to outcome in a series of 427 patients prospectively studied in an international, multicenter, randomized, double-blind trial of the N-methyl-D-aspartate antagonist Selfotel. Mortality rates rose from 9.6% in 292 patients who had no clinically defined episodes of neurological deterioration to 56.4% in 117 patients who suffered one or more of these episodes; 18 patients were lost to follow up. Correspondingly, favorable outcome, defined as good or moderate on the Glasgow Outcome Scale at 6 months, fell from 67.8% in patients without neurological deterioration to 29.1% in those with neurological deterioration. In patients who had clinical evidence of neurological deterioration, the relative influence of ICP and CPP on outcome was assessed. The most powerful predictor of neurological worsening was the presence of intracranial hypertension (ICP > or = 20 mm Hg) either initially or during neurological deterioration. There was no correlation with the CPP as long as the CPP was greater than 60 mm Hg. CONCLUSIONS: Treatment protocols for the management of severe head injury should emphasize the immediate reduction of raised ICP to less than 20 mm Hg if possible. A CPP greater than 60 mm Hg appears to have little influence on the outcome of patients with severe head injury.

Adolescent↗
PubMed1999

Dual action of the adenovirus E1A 243R oncoprotein on the human proliferating cell nuclear antigen promoter: repression of transcriptional activation by p53.

The promoter of the human proliferating cell nuclear antigen (PCNA) gene is activated by the adenovirus oncoprotein E1A 243R in HeLa cells. To understand the effect of this oncoprotein on PCNA expression in cells that are sensitive to oncogenic transformation by adenovirus, we studied the effect of E1A 243R on PCNA promoter-directed reporter gene expression in cloned rat embryo fibroblast (CREF) and primary baby rat kidney cells. In contrast to the results obtained in HeLa cells, E1A repressed the PCNA promoter in both cell-types. Promoter analysis identified a p53-responsive element that mediates E1A-induced repression. Repression required the intact N-terminus of E1A 243R, as shown by the ability of mutant E1A proteins to repress the promoter, and correlated with the p300-binding region of E1A. The adenovirus E1B 19K protein relieved repression by E1A 243R. These results reveal dual pathways for induction of this essential DNA replication factor and suggest a mechanism for oncogenic cooperativity between the E1A and E1B oncoproteins.

Adenovirus E1A Proteins↗
PubMed1999

Activation of Bcl-2 promoter-directed gene expression by the human immunodeficiency virus type-1 Tat protein.

Human immunodeficiency virus type 1 (HIV-1) Tat transcriptionally activates expression from a number of viral and cellular promoters. Recent studies demonstrate the ability of Tat to differentially modulate cellular responses to apoptotic signaling. The antiapoptotic effects of Tat appear to correlate with increased expression of Bcl-2, a cellular protein that enhances cellular survival. Here, endogenous expression of HIV-1 Tat in HeLa and Jurkat cells elevates levels of Bcl-2. Transient expression assays performed in HeLa cells demonstrate that Tat directly or indirectly enhances Bcl-2 promoter-directed gene expression by more than 10-fold. Analyses of Tat mutants demonstrate that two noncontiguous regions in the N- and C-termini of Tat mediate maximal transactivation of the Bcl-2 promoter. The requirement for C-terminal sequences contrasts with transactivation of the HIV-1 long terminal repeat in which the N-terminal 57 amino acids are required but downstream residues are not. Bcl-2 promoter analyses suggest that sequences required for Tat responsiveness are located upstream of P1 and between the P1 and P2 promoter units. Results from these studies reveal effects of HIV-1 Tat on Bcl-2 expression and provide a putative mechanism by which endogenously expressed Tat affects cellular survival through the up-regulation of Bcl-2.

Binding Sites↗
PubMed1999

The frequency, antecedent events, and causal relationships of neurologic worsening following severe head injury. Executive Committee of the international Selfotel Trial.

Neurologic deterioration observed following head injury is recognized as having a deleterious effect on outcome. The present study examines this occurrence in detail to determine the frequency of these episodes, their antecedent events and causal relationships in order to identify patients who are at risk. Data was collected prospectively from a consecutive series of 427 patients entered into the international trial of the NMDA receptor antagonist Selfotel. Using a definition of neurologic worsening based upon objective criteria, 117 patients were identified who suffered 164 episodes of deterioration. The occurrence of a single episode of neurologic worsening increased mortality by more than five-fold and reduced favorable outcomes (good or moderate on the Glasgow Outcome Scale), by more than 50%. Increased intracranial volume resulting in intracranial hypertension was the single most frequent cause of neurologic worsening. This serves to emphasize the importance of more adequate treatments of intracranial hypertension in improving the outcome of patients with severe head injury.

Adolescent↗
PubMed1999

Emphysematous lesions, inflammation, and fibrosis in the lungs of transgenic mice overexpressing platelet-derived growth factor.

Because of its expression pattern and its potent effects on mesenchymal cells, platelet-derived growth factor (PDGF) has been implicated as an important factor in epithelial-mesenchymal cell interactions during normal lung development and in the pathogenesis of fibrotic lung disease. To further explore the role of PDGF in these processes, we have developed transgenic mice that express the PDGF-B gene from the lung-specific surfactant protein C (SPC) promoter. Adult SPC-PDGFB transgenic mice exhibited lung pathology characterized by enlarged airspaces, inflammation, and fibrosis. Emphysematous changes frequently occurred throughout the lung, but inflammation and fibrotic lesions were usually confined to focal areas. The severity of this phenotype varied significantly among individual mice within the same SPC-PDGFB transgenic lineage. A pathology similar to that observed in adult mice was noted in lungs from transgenic mice as young as 1 week of age. Neonatal transgenic mice exhibited enlarged saccules and thickened primary septa. Results of these studies indicated that overexpression of PDGF-B induced distinct abnormalities in the developing and adult lung and led to a complex phenotype that encompassed aspects of both emphysema and fibrotic lung disease.

Age Factors↗
PubMed1999

p53-mediated regulation of proliferating cell nuclear antigen expression in cells exposed to ionizing radiation.

The proliferating cell nuclear antigen (PCNA) is a highly conserved cellular protein that functions both in DNA replication and in DNA repair. Exposure of a rat embryo fibroblast cell line (CREF cells) to gamma radiation induced simultaneous expression of PCNA with the p53 tumor suppressor protein and the cyclin-dependent kinase inhibitor p21(WAF1/Cip1). PCNA mRNA levels transiently increased in serum-starved cells exposed to ionizing radiation, an observation suggesting that the radiation-associated increase in PCNA expression could be dissociated from cell cycle progression. Irradiation of CREF cells activated a transiently expressed PCNA promoter chloramphenicol acetyltransferase construct through p53 binding sequences via a mechanism blocked by a dominant negative mutant p53. Electrophoretic mobility shift assays with nuclear extracts prepared from irradiated CREF cells produced four p53-specific DNA-protein complexes with the PCNA p53 binding site. Addition of monoclonal antibody PAb421 (p53-specific) or AC238 (specific to the transcriptional coactivator p300/CREB binding protein) to the mobility shift assay distinguished different forms of p53 that changed in relative abundance with time after irradiation. These findings suggest a complex cellular response to DNA damage in which p53 transiently activates expression of PCNA for the purpose of limited DNA repair. In a population of nongrowing cells with diminished PCNA levels, this pathway may be crucial to survival following DNA damage.

Animals↗
PubMed1999

Failure of the competitive N-methyl-D-aspartate antagonist Selfotel (CGS 19755) in the treatment of severe head injury: results of two phase III clinical trials. The Selfotel Investigators.

OBJECT: Excessive activity of excitatory amino acids released after head trauma has been demonstrated to contribute to progressive injury in animal models and human studies. Several pharmacological agents that act as antagonists to the glutamate receptor have shown promise in limiting this progression. The efficacy of the N-methyl-D-aspartate receptor antagonist Selfotel (CGS 19755) was evaluated in two parallel studies of severely head injured patients, defined as patients with post resuscitation Glasgow Coma Scale scores of 4 to 8. METHODS: A total of 693 patients were prospectively enrolled in two multicenter double-blind studies. Comparison between the treatment groups showed no significant difference with regard to demographic data, previous incidence of hypotension, and severity of injury. As the study progressed, the Safety and Monitoring Committee became concerned about possible increased deaths and serious brain-related adverse events in the treatment arm of the two head injury trials, as well as deaths in the two stroke trials being monitored concurrently. The Selfotel trials were stopped prematurely because of this concern and because an interim efficacy analysis indicated that the likelihood of demonstrating success with the agent if the studies had been completed was almost nil. CONCLUSIONS: Subsequently, more complete data analysis revealed no statistically significant difference in mortality rates in all cases between the two treatment groups in the head injury trials. In this report the authors examine the studies in detail and discuss the potential application of the data to future trial designs.

Adult↗
PubMed1998

Spinal hamartomas: a distinct clinical entity.

OBJECT: Congenital spinal hamartomas are defined as tumors of well-differentiated mature elements situated in an abnormal location. In this report, the authors document the clinical and pathological features of spinal hamartomas in 10 patients. METHODS: Ten patients presented with midline dorsal malformations at birth, initially diagnosed as teratomas or myelomeningoceles. The locations of the masses were variable: two were located in the thoracic region, four at the thoracolumbar junction, two in the lumbar region, one at the lumbosacral junction, and one in the sacral region. The results of the neurological examination were normal in nine patients. All but one mass had intact skin and seven had palpable bone components. Neuroimaging studies revealed widening of the spinal canal, heterotopic bone located dorsally in some patients, and varying degrees of involvement of the intraspinal contents. During surgery, six patients were found to have involvement of the spinal cord or cauda equina. The pathological characteristics of the masses included three or more of the following: bone, cartilage, synovial membrane, urinary tract tissue, cyst wall, yellow or brown fat, and nerves. The well-differentiated cellular elements, which formed mature structures, along with the absence of primitive cellular components and neoplastic characteristics are more consistent with a diagnosis of hamartoma than teratoma. CONCLUSIONS: In this series, the authors describe a lesion that is overt on physical examination, yet can have occult spinal canal involvement. Complete neurosurgical evaluation is essential to provide appropriate treatment and prognosis.

Adipose Tissue↗
PubMed1998

A multicenter trial on the efficacy of using tirilazad mesylate in cases of head injury.

OBJECT: The authors prospectively studied the efficacy of tirilazad mesylate, a novel aminosteroid, in humans with head injuries. METHODS: A cohort of 1120 head-injured patients received at least one dose of study medication (tirilazad or placebo). Eighty-five percent (957) of the patients had suffered a severe head injury (Glasgow Coma Scale [GCS] score 4-8) and 15% (163) had sustained a moderate head injury (GCS score 9-12). Six-month outcomes for the tirilazad- and placebo-treated groups for the Glasgow Outcome Scale categories of both good recovery and death showed no significant difference (good recovery in the tirilazad-treated group was 39% compared with the placebo group in which it was 42% [p=0.461]; death in the tirilazad-treated group occurred in 26% of patients compared with the placebo group, in which it occurred in 25% [p=0.750]). Subgroup analysis suggested that tirilazad mesylate may be effective in reducing mortality rates in males suffering from severe head injury with accompanying traumatic subarachnoid hemorrhage (death in the tirilazad-treated group occurred in 34% of patients; in the placebo group it occurred in 43% [p=0.026]). No significant differences in frequency or types of serious adverse events were shown between the treatment and placebo groups. CONCLUSIONS: Striking problems with imbalance concerning basic prognostic variables were observed in spite of the large population studied. These imbalances concerned pretreatment hypotension, pretreatment hypoxia, and the incidence of epidural hematomas. In future trials of pharmacological therapy for severe head injury, serious consideration must be given to alternative randomization strategies. Given the heterogeneous nature of head injury and the identification of populations that do relatively well with standard therapy, target populations with a higher risk for mortality and morbidity may be more suitable for clinical trials of such agents.

Adult↗
PubMed1998

Direct cochlear nerve monitoring: first report on a new atraumatic, self-retaining electrode.

OBJECTIVE: To assess the efficacy and safety of a new atraumatic, self-retaining cranial nerve electrode for direct cochlear nerve monitoring during cerebellopontine angle surgery. STUDY DESIGN: Prospective clinical investigation. SETTING: The Skull Base Surgery Center at Kaiser Permanente, San Diego, a tertiary referral center for neurotologic and skull-base surgery within Southern California Permanente Medical Group. PATIENTS: Eighteen patients, with aidable preoperative hearing, underwent direct cochlear nerve monitoring with this new electrode during cerebellopontine angle surgery for a variety of diagnoses. METHODS: Intraoperative observations of cochlear nerve action potential amplitude and latency were recorded. Preoperative and 1-month postoperative audiograms were compared to assess the degree of hearing preservation. Postoperative facial nerve function was assessed using the House-Brackmann method. RESULTS: Good auditory function was preserved in four of eight acoustic tumors, with poor hearing preserved in two additional patients. Good auditory function was preserved in the remaining ten patients. Cochlear nerve action potential amplitudes between 5 and 70 microV were recorded. Postoperative facial nerve function was House-Brackmann class I-II in all 18 patients. CONCLUSION: The authors find this new electrode to be safe and effective for monitoring cochlear nerve function during cerebellopontine angle surgery.

Cerebellopontine Angle↗
PubMed1998

Lung-specific expression in mice of a dominant negative mutant form of the p53 tumor suppressor protein.

Lung cancer is the most frequent cause of cancer deaths in the United States. A strong correlation exists between mutations in the gene encoding the p53 tumor suppressor protein and lung malignancies. Our goal is to prepare a transgenic mouse model with disrupted p53 function in the epithelial cells of the peripheral lung. To achieve this goal, a "dominant negative" mutant form of p53 was expressed from the human surfactant protein C (SPC) promoter. The dominant negative p53 expressed from the SPC promoter will antagonize wild-type p53 functions in alveolar type II pneumocytes and some bronchiolar cells of the transgenic animals and thereby promote development of carcinoma of the lung. This animal model should prove useful to the study of lung carcinogenesis and to the identification of agents that contribute to neoplastic conversion in the lung.

Animals↗
PubMed1998

Neurological deterioration as a potential alternative endpoint in human clinical trials of experimental pharmacological agents for treatment of severe traumatic brain injuries. Executive Committee of the International Selfotel Trial.

OBJECTIVE: A recently improved understanding of the pathophysiological features of head injuries has led to the development of new drug therapies. Accurate human clinical trials remain necessary to document the efficacy and safety of new agents. It would be helpful to decrease the time from drug development to clinical use and general availability for drugs found to be effective. Conversely, ineffective agents could be abandoned in a timely fashion. RATIONALE: A new endpoint measure, defined as neuroworsening (NW), is an objective observable event that is identifiable during hospitalization. This may enable the efficacy of drugs to be demonstrated or disproved much earlier than with 6-month outcome assessments. The prospective, double-blind, multicenter trial of the N-methyl-D-aspartate receptor antagonist Selfotel was used to acquire data on the efficacy of NW in predicting neurological outcomes. The 6-month Glasgow Outcome Scale scores, which were the primary endpoints of that trial, were compared with the frequency of NW. NW was an observable event that could be objectively defined after head injuries. Patients who suffered one or more episodes of NW demonstrated significantly higher morbidity and mortality rates than did patients who did not. CONCLUSION: Future trials should consider the use of NW as an outcome measure that can be included with more traditional measures in the study design. If the strong correlation demonstrated between NW and 6-month Glasgow Outcome Scale scores can be prospectively demonstrated in a successful trial, the time to approval of future agents could be decreased.

Adult↗