Search PubMed⌕ Search

Biomedical subjects

D P Becker

Publications and source records attributed to D P Becker.

At least 37 records · Page 2Linked to original sources
PubMed1997

The herpesvirus protease: mechanistic studies and discovery of inhibitors of the human cytomegalovirus protease.

The herpesvirus protease is a recently identified enzyme which is essential for viral replication. It is found in all herpesviruses and offers a new molecular target for therapeutic intervention. Its genomic structure has recently been described and consists of a large open reading frame which encodes a fusion protein containing an amino-terminal protease domain in-frame with a carboxyl-terminal "assembly protein-like" domain. Auto-processing releases the amino-terminal protease as a maturational enzyme. The herpesvirus protease has been characterized as a novel serine protease. Four surface accessible sulfhydryl groups have been identified in the human cytomegalovirus (HCMV) protease. Utilizing a fluorogenic DABCYL-EDANS substrate assay, directed screening has identified a class of sulfhydryl-modifying benzimidazolylmethyl sulfoxides which inhibits recombinant HCMV protease. Site-directed mutagenesis studies suggest oxidative modification of surface-accessible HCMV protease Cys138 (and possibly Cys161) by this class of inhibitors. The benzimidazolylmethyl sulfoxide 1 inhibits HCMV protease (IC50 = 1.9 microM), exhibits selectivity vs. mammalian serine proteases, and exhibits antiviral activity in an HCMV infected cell culture assay.

Antiviral Agents↗
PubMed1996

Fluid percussion brain injury in the developing and adult rat: a comparative study of mortality, morphology, intracranial pressure and mean arterial blood pressure.

Changes in intracranial pressure (ICP) and mean arterial blood pressure (MABP) were measured for 30 min following an experimental fluid percussion traumatic brain injury in postnatal day 17 (P17), P28 and adult rats. Under enflurane anesthesia the left femoral artery was cannulated for MABP measurements and a 20 gauge needle was stereotaxically positioned into the right lateral ventricle for ICP measurements. Three different injury severities (mild: 1.35-1.45 atm, moderate: 2.65-2.75 atm, severe: 3.65-3.75 atm) were delivered over the left parietal cortex to each of the age groups. The biomechanical/physiological results indicated that fluid percussion generated reproducible traumatic brain injuries in the developing rat. Furthermore, with increasing injury severity the physiological responses (in terms of ICP and MABP) became more pronounced, resulting in a corresponding increase in mortality (mild, moderate, severe, respectively, P17: 27%, 36%, 100%; P28: 33%, 30%, 75%; adult: 0%, 20%, 55%). Compared to adult animals, developing rats exhibited pronounced hypotension in response to closed head injury, which most likely explains the greater percent mortality among the younger animals. The utilization of this model will allow for future studies addressing the consequences of traumatic brain injury when it is sustained early in development.

Analysis of Variance↗
PubMed1996

Microsurgical management of giant pituitary tumors.

Pituitary turnors with large suprasellar extensions are a difficult surgical challenge. A series of 11 patients with giant pituitary adenomas is reported. Seven men and four women (mean age 54.1 years). were diagnosed following a mean duration of symptoms of 60 months, Common presenting symptoms included visual disturbances, headache, personality changes, and panhypopituitarism. A single patient presented with rapid onset of coma and oculomotor nerve palsy. Eight patients underwent a transsphenoidal approach, and three patients underwent a craniotomy as the initial surgical procedure. A total of 16 surgical procedures were performed, resulting in complete or near complete resection in seven patients, and partial removal in four. Six patients had a good outcome and one patient in poor condition prior to surgery was unchanged postoperatively. One patient was worse following surgery, and there were two operative deaths. These tumors have a consistency and a propensity to adhere to neurovascular structures, making complete surgical resection difficult. Management should be individualized and should be based upon the radiographic and clinical features of the tumor. We feel that most leslons are best approached initially transsphenoidally, unless there is significant lateral extension. In many patients, aggressive surgery is not indicated and limited subtotal transsphenoidal resection followed by irradiation is recommended. Surgical decision making and strategy is discussed in relation to our recent experience with giant pitnitary adenomas.

Journal Article↗
PubMed1996

A continuous microneurosurgical irrigation and suction system: technical note.

OBJECTIVE: We describe a continuous microneurosurgical irrigation and suction technique. This technique automatically clears the operative field, frees the surgeon to perform microdissection with both hands, and actually aids in dissection of the arachnoid layer. TECHNIQUE: The suction catheter (MicroVac; P.M.T., Inc., Hopkins, MN) described by Spetzler and Iverson and an additional continuous microirrigation technique are discussed. The catheter design has a sump effect and is secured in a dependent position in the operative field to continuously remove blood, irrigate the area, and reduce cerebrospinal fluid accumulation. The irrigation system consists of standard intravenous tubing with an angiocatheter used to direct a precise stream into the operative field. RESULTS AND CONCLUSION: The irrigation and suction system, when properly adjusted, continuously clears the operative site of minute amounts of blood that may obscure the surgeon's view and assists in dissection of the arachnoid layer. It has been used since 1991 with excellent success and satisfaction.

Arachnoid↗
PubMed1996

Hyperemia following traumatic brain injury: relationship to intracranial hypertension and outcome.

The role of posttraumatic hyperemia in the development of raised intracranial pressure (ICP) has important pathophysiological and therapeutic implications. To determine the relationship between hyperemia (cerebral blood flow (CBF) > 55 ml/100 g/minute), intracranial hypertension (ICP > 20 mm Hg), and neurological outcome, 193 simultaneous measurements of ICP and CBF (xenon-133 method) were obtained in 59 patients with moderate and severe head injury. Hyperemia was associated with an increased incidence of simultaneous intracranial hypertension compared to nonhyperemic CBF measurements (32.2% vs. 21.6%, respectively; p < 0.059). However, in 78% of blood flow studies in which ICP was greater than 20 mm Hg, CBF was less than or equal to 55 ml/100 g/minute. At least one episode of hyperemia was documented in 34% of patients, all of whom had a Glasgow Coma Scale (GCS) score of 9 or below. In 12 individuals with hyperemia without simultaneous intracranial hypertension, ICP was greater than 20 mm Hg for an average of 11 +/- 16 hours and favorable outcomes were seen in 75% of patients. In contrast, in eight individuals with hyperemia and at least one episode of hyperemia-associated intracranial hypertension, ICP was greater than 20 mm Hg for an average of 148 +/- 84 hours (p < 0.001), and a favorable outcome was seen in only one patient (p < 0.001). Compared to the remainder of the cohort, patients with hyperemia-associated intracranial hypertension were distinctive in being the youngest, exhibiting the lowest GCS scores (all < or = 6), and having the highest incidence of effaced basilar cisterns and intractable intracranial hypertension. In the majority of individuals with hyperemia-associated intracranial hypertension, their clinical profile suggests the occurrence of a severe initial insult with resultant gross impairment of metabolic vasoreactivity and pressure autoregulation. In a minority of these patients, however, high CBF may be coupled to a hypermetabolic state, given their responsiveness to metabolic suppressive therapy. In patients with hyperemia but without intracranial hypertension, elevated CBF is also likely to be a manifestation of appropriate coupling to increased metabolic demand consistent with a generally favorable outcome. This study supports the concept that there are multiple etiologies of both elevated blood flow and intracranial hypertension after head injury.

Adult↗
PubMed1995

Lactate accumulation following concussive brain injury: the role of ionic fluxes induced by excitatory amino acids.

During the first few minutes following traumatic brain injury, cells are exposed to an indiscriminate release of glutamate from nerve terminals resulting in a massive ionic flux (e.g., K+ efflux) via stimulation of excitatory amino acid (EAA)-coupled ion channels. The present study was undertaken to elucidate the causal relationship between these ionic shifts and lactate accumulation in the injured brain, by examining the effects of ouabain (an inhibitor of Na+/K+-ATPase), Ba2+ (an inhibitor or non-energy-dependent glial K+ uptake) and kynurenic acid (KYN; a broad-spectrum EAA antagonist) on lactate accumulation. Two microdialysis probes were placed bilaterally in the rat parietal cortex. One was perfused with a test drug (1.0 mM ouabain, 2.0 mM Ba2+ or 10 mM KYN) and the other with Ringer's solution (control) for 30 min prior to injury. Following a 2.2-2.7 atm fluid-percussion injury, lactate levels in the dialysate increased (up to 116.6% above baseline) for the first 16 min and returned to baseline levels within 20 min after injury. This lactate accumulation was attenuated by preinjury administration of ouabain and KYN and was prolonged by Ba2+ administration. These findings indicate that lactate accumulations following concussive brain injury is a result of increased glycolysis which supports ion-pumping mechanisms, thereby, restoring the ionic balance which was disrupted by stimulation of EAA-coupled ion channels.

Animals↗
PubMed1995

Vascular compression syndrome of the vestibular nerve: a critical analysis.

The rationale, indications, and surgical results of microvascular decompression for the treatment of vertigo are reviewed, and a critical analysis is made. The syndrome of disabling positional vertigo is discussed. It is concluded that (1) vascular compressive vestibular neuropathy may exist, (2) the current published diagnostic criteria for this disorder are insufficient to firmly establish the diagnosis, and (3) further work delineating this syndrome should be undertaken.

Brain↗
PubMed1994

Four-year follow-up of adrenal-to-brain transplants in Parkinson's disease.

OBJECTIVE: Evaluate long-term efficacy of autologous adrenal-to-caudate transplants in idiopathic Parkinson's disease refractory to medical treatment. DESIGN: Subjects underwent evaluations several times preoperatively on the University of California-Los Angeles Parkinson's Disease Disability Scale and the Hoehn and Yahr stage of disease. Postoperatively, they were also repeatedly rated on the Unified Parkinson's Disease Rating Scale. SETTING: Clinical visits and surgery took place at the University of California-Los Angeles Center for the Health Sciences. PATIENTS: Three men and one woman, ages 44 to 55 years, were followed up for several years preoperatively. At surgery, disease durations ranged from 7 to 16 years. Originally, all patients had a good response to levodopa, but for several years preoperatively, they had had fluctuating responses and a short duration of drug action. INTERVENTION: Right adrenalectomy was performed through a midline abdominal incision. Open craniotomy exposed the head of the right caudate into which pieces of adrenal medulla, 1 to 2 mm in size, were implanted. MAIN OUTCOME MEASURES: Scores on the three major scales (see "Design") were augmented with the number of hours "off" per day and severity of abnormal involuntary movements. Disease progression of each patient was compared with his own preoperative course and with those of a cohort of patients with Parkinson's disease followed up for 14 years who had received medical treatment without transplant surgery. RESULTS: After 4 years, transplants continued to be beneficial to three patients and had been of brief transient benefit to the fourth. The course of disease was more benign postoperatively than preoperatively and was more slowly progressive than that in the cohort. CONCLUSION: Improvement was not sufficient to justify adrenal transplants as routine therapy but does point the way to the use of other dopamine tissue transplantation.

Adrenal Cortex↗
PubMed1994

Metabolic alterations accompany ionic disturbances and cellular swelling during a hypoxic insult to the retina: an in vitro study.

To study the ionic, metabolic, and morphologic derangements that occur following brain injury we utilized a retina in vitro model of hypoxia. Retinas were dissected into oxygenated (95% O2, 5% CO2) Ames medium, a physiologic solution resembling cerebrospinal fluid, and randomly assigned to either experimental hypoxic conditions (95% N2, 5% CO2) or control conditions. All retinas were incubated and maintained at 37 degrees C. Changes in extracellular K+ and lactate concentration, intracellular incorporation of 45Ca and 14C-leucine, uptake of glucose using [14C]-2-deoxy-D-glucose (2DG), and cell size were determined at 10, 20, 30, and 60 minute time intervals. The results show that compared to control retinas hypoxia produced: (1) an early increase in extracellular concentration of K+ and lactate, (2) a delayed increase in the intracellular incorporation of 45Ca, (3) an early onset of cellular swelling, and (4) a decrease in the intracellular incorporation of 14C-leucine, and (5) increased glucose utilization. All of the results were statistically significant (p < 0.05) and exhibited a dose response relationship with the exception of intracellular incorporation of 45Ca which did not become significantly different until 30 minutes post-hypoxia. A 16% increase in cell size was noted after 10 minutes of hypoxia. Increased hypoxic cell size persisted for 30 minutes but after 60 minutes the control retinas appeared enlarged as well. Our results suggest that ionic, metabolic, and morphologic derangements can be demonstrated utilizing an in vitro model of hypoxia which are similar to those seen following in vivo traumatic brain injury. With use of this model the mechanisms behind these ionic-metabolic relationships can be addressed at the molecular level.

Animals↗
PubMed1994

Metabolic changes following cortical contusion: relationships to edema and morphological changes.

Rats with contusion injury to the right cortex exhibited significant formation of edema 6 and 24 hours after injury which resolved by 8 days and was replaced by cavitation necrosis. The contusions produced hyperglycolysis and ischemia in the impacted cortical tissue and underlying hippocampus immediately through 30 minutes post-injury. Glucose utilization was depressed throughout the contused cortex and in ipsilateral subcortical regions, as was blood flow, at chronic (1 and 10 days) periods after injury.

Animals↗
PubMed1994

Regional cerebral blood flow trends in head injured patients with focal contusions and cerebral edema.

Focal contusions following head injury may be associated with focal or diffuse cerebral edema. Early global hyperemia and perifocal hyperemia may play a role in cerebral edema, although causal relationships have yet to be clearly been defined. We studied 27 patients with head injury (admission GCS 3-12) resulting in focal contusions (without evidence of subarachnoid, intraventricular or intraparenchymal hemorrhage by CT). Patients were studied with ICP monitors, head CTs, and intravenous 133Xenon regional cerebral perfusion studies serially over several days post injury. Low cortical blood flow and a low mean CBF15 flow were evident on the day of the injury. Additionally, F1 analysis indicated significantly (p < 0.05) greater cortical blood flow in the surrounding brain (mean 60 cc/100 g/min) compared to the contusion area (mean 43 cc/100 g/min) on the day of trauma. Mean regional CBF remained below normal in the contused areas (CBF15 < 35 cc/100 g/min), however the cortical flow increased in the first few days post-injury (peak F1 = 95 cc/100 g/min on day 3) then decreased to sub-normal levels. The mean CBF in the surrounding brain was low on the day of injury (CBF15 = 29 cc/100 g/min), although higher than the contused area, and increased to a peak of 45 cc/1009/min on day 3 posttrauma. Cortical flow in the surrounding brain, however, exhibited a different trend. The mean F1 was low on the day of trauma and significantly higher one day after trauma (mean 105 cc/100 g/min). Only 15 of the 27 patients with focal contusions had evidence of cerebral edema. Eleven of these exhibited focal edema and 4 exhibited diffuse edema. Focal edema developed over the first few days posttrauma as seen in followup CT, whereas patients with diffuse edema exhibited edema on the admission CT. Initial oligemia in the contused areas was associated with a subsequent hyperemic rim about the contusion. Focal hyperemia was associated with focal edema in 41% of the patients, whereas diffuse edema appeared to be independent of the hyperemic response in contusions.

Adolescent↗
PubMed1994

Administration of an omega-conopeptide one hour following traumatic brain injury reduces 45calcium accumulation.

The omega-conopeptide, SNX-111 (NEUREX Corporation) was administered to rats 1 hour following a lateral fluid percussion brain injury to determine if the drug could reduced the extent and duration of trauma-induced calcium accumulation. Administration at doses of 3 or 5 mg/kg (i.v.) markedly reduced the extent of calcium accumulation as determined using 45calcium autoradiography primarily within the cerebral cortex and hippocampus. The reduction of calcium accumulation was particularly event within the parietal cortex beginning as early as 6 hours and lasting out to 48 hours following injury. Although not as effective as in the cerebral cortex, SNX-111 did exhibit a reduction of calcium accumulation within the dorsal hippocampus especially at 24 and 48 hours after the insult. These preliminary results demonstrate that SNX-111 can reduce the injury-induced accumulation of calcium even when administered 1 hour after the insult and offers this compound as a potential therapeutic treatment for traumatic brain injury.

Animals↗
PubMed1994

Peripheral benzodiazepine stimulates secretion of growth hormone and mitochondrial proliferation in pituitary tumour GH3 cells.

High affinity receptors for peripheral benzodiazepines (PBD) are present within the pituitary gland. Whether these receptors influence cell growth, mitochondrial morphology and secretion of growth hormone was examined in pituitary tumour GH3 cells. Cells were incubated in medium with either 10% calf serum, or serum free medium, or serum free medium plus 10 nM of selective PBD ligands (PK11195 or Ro5-4864) or a central benzodiazepine ligand (clonazepam). Peripheral or central ligands had no effect on cell growth. Quantitative electron micrography, however, revealed that cells treated with PBDs had a 2.5-fold increase in the total mitochondrial area within cells, a 1.6-fold increase in the number of mitochondria, and a 2.0 to 2.7-fold increase on the number of dividing mitochondria compared to serum free controls. The activity of DNA polymerase gamma, which replicates mitochondrial DNA, was increased approximately 3 times the initial value after 6 h exposure to PBDs. The number of nucleolar organizer regions (NORs), which relate to the ultimate synthesis of cellular protein, showed a 1.4-fold increase in PBDs treated cells. Secretion of growth hormone was stimulated (240% of serum free control) by exposure to PBDs for 12 h. The central benzodiazepine ligand, clonazepam, had little effect on mitochondrial morphology or secretion of growth hormone. These findings suggest that PBD receptors may be involved in mitochondrial proliferation and may affect the secretion of pituitary hormones.

Adenoma↗
PubMed1994

Thallium-201 SPECT and positron emission tomography equal predictors of glioma grade and recurrence.

Quantitative indexes based on regions of interest ratios from preoperative thallium-201 SPECT and F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) scans were compared for their ability to predict the histological grade of cerebral gliomas. Of the five different ratios used to determine the index for each PET scan, the ratio of tumour versus ipsilateral hemisphere in the same plane as the tumour showed the most significant correlation with glioma grade (p < 0.001). A large study of 62 thallium-201 SPECT scans showed equally good correlation with glioma grade (p < 0.0005). The use of thallium-201 SPECT for detection of tumour recurrence had 100% sensitivity in this series, while PET scans had 90.9% sensitivity. Patients with a rate of change in serial thallium indexes of 0.475 +/- 0.278 per month survived 5.93 +/- 2.25 months from onset of index increase, while those with little change in the index (0.069 +/- 0.063 per month) survived 17.93 +/- 5.25 months from onset of index increase. Results indicate thallium-201 SPECT correlates well with tumour grade and is equally efficient as PET in screening for glioma recurrence.

Brain Neoplasms↗
PubMed1994

The neurosurgical intensive care unit in an era of health care reform.

Health care reform, public concern, and managed care will create an environment that demands highly creative strategies to deliver quality care while reducing costs. Patient satisfaction and outcomes will take on a high priority. To meet this challenge, the neurosurgical ICU of the future will be designed with a patient-focused theme wherein the physical environment embodies healing and humanism. Services will be brought to the patient rather than the patient accommodating the system. Patients and families will be the directors of their own care. Staff and families will have access to a highly sophisticated clinical information system, and learning for staff at all levels will be a part of everyday life in the ICU. Unit management will be within a framework of shared governance wherein the power base is with the direct care givers, and decision and policy making happens at the point closest to the patient. Patient outcomes will be a result of a highly organized collaborative model that includes primary nursing, critical paths, and case management. Partnerships between nurses and unit support staff will create skill-mix changes that allow the nurse to spend less time on nonclinical unit maintenance-type functions and more time with the patient and family. This will have a positive fiscal impact as well as enhance patient satisfaction and outcomes.

Cost-Benefit Analysis↗
PubMed1993

Concussive brain injury is associated with a prolonged accumulation of calcium: a 45Ca autoradiographic study.

In order to determine the extent and duration of calcium (Ca2+) flux following a lateral fluid percussion brain injury in the rat, 45Ca autoradiography was used to study animals immediately, 6, 24 and 96 h after the insult. In addition, cell suspension studies were conducted to determine the extent of cellular flux of 45Ca. Optical density and/or scintillation counting was utilized to provide a relative measure of 45Ca accumulation within 20 different structures. The results indicated that in animals who exhibited no gross morphological damage, 45Ca accumulation following injury was exhibited primarily within the ipsilateral cerebral cortex, dorsal hippocampus and striatum. This accumulation continued for several days returning to control levels by the 4th day after injury. In animals who sustained morphological damage, the contusion site exhibited a marked accumulation of 45Ca which did not resolve spontaneously over the course of 4 days. We conclude from this work that Ca2+ flux is a major component of this experimental model of traumatic injury. Furthermore, that depending on the extent of cell damage, the accumulation of Ca2+ is regionally different. Finally, that even in an injury which by itself does not produce gross morphological tissue damage, accumulation of Ca2+ can continue for at least 48 h.

Animals↗
PubMed1993

Traumatic brain injury produces impairments in long-term and recent memory.

Traumatic brain injury (TBI) in humans typically produces neurological suppression and a longer lasting impairment of memory clinically defined as post-traumatic amnesia. An animal model that reliably reproduces the physiological changes associated with TBI was used to assess the memory deficits following brain injury. Prior to TBI, rats were trained to perform one of four tasks that assessed either motor performance, long-term or recent memory. Rats were randomly assigned to one of three groups (anesthesia only, sham operation or fluid percussion). Following fluid percussion, used to produce TBI, rats were tested for 6 test sessions. The first session occurred 1-2 min after the experimental manipulation. The next 5 sessions followed the training schedule maintained prior to experimental manipulation. Differences in long-term memory occurred only in the first post-operative test session. Differences in recent memory performance were found across all 6 test sessions. The memory deficits were clearly dissociated from motor deficits. The similar memory deficits observed following human head injury and the experimentally produced TBI injury demonstrate that fluid percussion is a useful approach to examine underlying neurobiological mechanisms involved in head injury and possible clinical interventions.

Animals↗