Activation of a signal transduction pathway by osteopontin.
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3T3 Cells↗
Biomedical subjects
R L Davis
Publications and source records attributed to R L Davis.
Prevention of autoimmune demyelination in non-human primates by a cAMP-specific phosphodiesterase inhibitor.
Experimental allergic encephalomyelitis (EAE) is an autoimmune disease of the central nervous system that serves as a model for the human disease multiple sclerosis. We evaluated rolipram, a type IV phosphodiesterase inhibitor, for its efficacy in preventing EAE in the common marmoset Callithrix jacchus. In a blinded experimental design, clinical signs of EAE developed within 17 days of immunization with human white matter in two placebo-treated animals but in none of three monkeys that received rolipram (10 mg/kg s.c. every other day) beginning 1 week after immunization. In controls, signs of EAE were associated with development of cerebrospinal fluid pleocytosis and cerebral MRI abnormalities. In the treatment group, there was sustained protection from clinical EAE, transient cerebrospinal fluid pleocytosis in only one of three animals, no MRI abnormality, and marked reduction in histopathologic findings. Rolipram-treated and control animals equally developed circulating antibodies to myelin basic protein. Thus, inhibition of type IV phosphodiesterase, initiated after sensitization to central nervous system antigens, protected against autoimmune demyelinating disease.
3',5'-Cyclic-AMP Phosphodiesterases↗
Kawasaki syndrome in Washington State. Race-specific incidence rates and residential proximity to water.
OBJECTIVES: To calculate race-specific incidence rates of Kawasaki syndrome (KS) and to assess the association of KS with residential proximity to water in Washington State. DESIGN: Incidence study over 4 1/2 years, using cases identified with a new statewide hospital data set and a case-control study. SETTING: King, Pierce, and Snohomish counties in Washington State. PATIENTS: One hundred twelve population-based incident cases meeting Centers for Disease Control and Prevention criteria for KS. MAIN OUTCOME MEASURES: Race-specific KS incidence rates and distance to permanent bodies of water among KS cases and matched controls. RESULTS: For the years 1985 through 1986 and 1987 through 1989, the annual KS incidence rates were 6.5 and 15.2 per 100,000 children younger than 5 years, respectively. Rates were highest among Asian Americans (33.3 per 100,000 children younger than 5 years in the 1987-1989 period), followed by blacks and whites (23.4 and 12.7 per 100,000 children younger than 5 years, respectively). The median distance to water did not differ between cases and controls and the proportion of cases living within 150 yd (135 m) of water was no greater than that of controls (odds ratio, 1.0; 95% confidence interval, 0.1 to 20.9). CONCLUSIONS: With complete ascertainment of incident-hospitalized cases of KS, the race-specific rates are among the highest documented in the United States. The rate among Asian Americans was less than that found in Japan, perhaps due to differences in environmental exposures or variations in susceptibility among different Asian ethnic groups. Although we found no association with permanent bodies of water, future studies of KS should include home inspection to assess exposure to temporary collections of standing water.
Black or African American↗
A mouse homolog of dunce, a gene important for learning and memory in Drosophila, is preferentially expressed in olfactory receptor neurons.
The dunce (dnc) gene in Drosophila codes for a cyclic adenosine monophosphate-specific phosphodiesterase (PDE). Flies with a mutation at this locus exhibit severe deficits in learning and memory. We have begun to analyze the neural distribution of mammalian homologs of dnc in the mouse. Surprisingly, in situ hybridization and northern blotting using a probe specific for one of the four mammalian dnc homologs (mPDE2) reveals high levels of expression in the olfactory neuroepithelium. Anti-mPDE2 antibody confirms that this PDE protein is abundant in the axons and dendrites of the olfactory receptor neurons but is conspicuously absent from the cilia, where the initial events in olfactory signal transduction occur. Lower levels of mPDE2 were also detected throughout the brain and in the testis. These findings suggest an important modulatory role for mPDE2 in mammalian olfaction.
Animals↗
Proliferation markers in gliomas: a comparison of BUDR, KI-67, and MIB-1.
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Biomarkers, Tumor↗
Heterogeneity, polyploidy, aneusomy, and 9p deletion in human glioblastoma multiforme.
The short arm of chromosome 9 is frequently deleted in malignant gliomas. We used locus-specific probes for interferon-A (IFNA) and D9S3 in combination with a chromosome 9 centromeric probe to detect genetic aberrations on a cell-by-cell basis in touch preparations of 30 glioblastomas by fluorescence in situ hybridization. Seven (23%) of 30 tumors had deletions in > 70% of cells; the IFNA locus was deleted in all seven, but the D9S3 locus was deleted in only five of the seven. The latter data confirm that a tumor suppressor gene on 9p relevant to glioblastoma multiforme lies between D9S3 and IFNA. Eleven tumors had deletions in 20-40% of cells, more than three standard deviations above the level in control tissues. The remaining tumors had deletions in < 20% of cells. The seven tumors with the lowest percentage of deleted cells each had more than one genetically abnormal population of cells. In total, 10 cases were of this type (i.e., aneusomic for chromosome 9). Three of these 10 tumors had hybridization patterns consistent with polyploidy.
Adult↗
Osteopontin expression detected in adult cochleae and inner ear fluids.
Localization of protein epitopes and mRNA expression showed that there was a wide-spread distribution of osteopontin (OPN) within the membranous labyrinth of the adult mammalian cochleae. Immunoreaction product and mRNA were found within the stria vascularis, VIIIth cranial nerve, spiral ligament and limbus. Only specific cell types within these regions contained abundant OPN mRNA or protein, the main cell type being fibrocytes that populate the spiral limbus and spiral ligament. Epithelial cells that line the luminal surface of the stria vascularis (marginal cells) and neurons that compose the vestibular and auditory ganglia also showed high opn expression. The pattern of anti-OPN staining within membranous labyrinth was comparable to that observed in tissues such as gall bladder, breast and kidney. In those tissues, luminal epithelial cells, corresponding to the marginal cells of the stria vascularis, may be responsible for manufacturing and secreting OPN into the luminal fluids. consistent with those observations, we detected OPN epitopes in cochlear fluids withdrawn from the scalae media and tympani of the cochlea. We found that the protein species in cochlear fluid differed from those present in cerebrospinal fluid (CSF) suggesting that OPN exists in tissue-specific isoforms that may correspond to particular cellular functions.
Animals↗
Subcutaneous sumatriptan for treatment of acute migraine in patients admitted to the emergency department: a multicenter study.
STUDY OBJECTIVE: To assess the efficacy of SC sumatriptan injection versus placebo in the treatment of acute migraine in ED patients and that of open-label 100 mg sumatriptan PO tablets for recurrent migraine. DESIGN: Randomized, double-blind, placebo-controlled, multi-center trial. SETTING: Twelve EDs in the United States. PARTICIPANTS: Adult patients presenting to the ED from September 1992 through April 1993 with a diagnosis of migraine as determined by International Headache Society criteria. Patients were randomized to receive 6 mg sumatriptan SC or placebo. Patients were monitored for improvement in headache severity using a four-point scale and for time to meaningful relief using a stopwatch. The time to discharge from the ED was recorded. An open-label 100 mg sumatriptan PO tablet was given to all patients on discharge from the ED for use at home if the headache recurred within 24 hours. RESULTS: One hundred thirty-six patients were enrolled. Seventy-five percent of patients treated with sumatriptan achieved meaningful relief compared with 35% treated with placebo (P < .001). The median time to meaningful relief was 34 minutes in the group that received sumatriptan. Seventy percent of patients in the sumatriptan group versus 35% in the placebo group reported mild or no pain at discharge (P < .001). Migraine-associated symptoms such as nausea, photophobia, and phonophobia were significantly reduced in the sumatriptan group (P < .005). The median time to discharge from the ED was shorter for the sumatriptan group than for the placebo group (60 versus 96 minutes, respectively; P = .001). At baseline, 15% of patients in the sumatriptan group and 19% of patients in the placebo group reported mild or no clinical disability. At the time of discharge, patients with mild or no disability increased to 75% in the sumatriptan group compared with 44% in the placebo group (P = .001). Fifty-seven of 92 patients (62%) with mild or no pain at discharge took open-label oral sumatriptan for headache recurrence, and 37 (65%) experienced meaningful relief within 2 hours. Median time to meaningful relief after oral sumatriptan was 65 minutes. CONCLUSION: Sumatriptan (6 mg SC) is effective in treating acute migraine in the ED. Oral sumatriptan (100 mg) is effective in treating headache recurrence within 24 hours.
Acute Disease↗
Vancomycin pharmacokinetics in spinal cord injured patients: a comparison with age-matched, able-bodied controls.
To compare the pharmacokinetics of vancomycin in chronic spinal cord injured patients and hospitalized, age-matched, able-bodied controls, we evaluated 14 spinal cord injured patients and 14 controls. Pharmacokinetic parameters of total body clearance (CL), distribution volume (V), elimination rate constant (k) and elimination half-life (t1/2) were calculated from two steady-state vancomycin serum concentrations by the method of Sawchuk and Zaske. Demographic data such as age, ideal body weight (IBW), total body weight (TBW) and serum creatinine at start of therapy (SCr), pharmacokinetic parameters and predicted dosages to achieve specific peak (30 mcg/ml) and through concentrations (5-10 mcg/ml) were calculated for both groups. Statistical comparisons were made using a two sample, Student's t-test. Demographic data between groups differed only in mean serum creatinine (p = 0.04). There were no statistically significant differences in mean pharmacokinetic parameters of CL and V or mean predicted dosages. Mean elimination rate constant was significantly smaller and mean elimination half-life was significantly longer in spinal cord injured patients (p = 0.02 and p = 0.04, respectively). The longer dosing interval predicted in spinal cord injured patients trended toward statistical significance (p = 0.10). We conclude that with chronic spinal cord injury, 1) the elimination half-life of vancomycin is increased and these patients may require longer dosing intervals and 2) distribution volume and predicted vancomycin doses are unaltered compared with controls.
Adult↗
Chondroid chordoma. A hyalinized chordoma without cartilaginous differentiation.
"Chondroid chordoma" is a controversial and confusing entity that was originally described by Heffelfinger and colleagues as a biphasic malignant neoplasm possessing elements of both chordoma and cartilaginous tissue. Because the premise for this distinction was based strictly on histomorphologic criteria, the light microscopic, immunohistochemical, and electron microscopic features of the chondroid and chordoid areas of five chondroid chordomas of the skull base were evaluated separately, and compared to five typical chordomas and six low grade chondrosarcomas. Using light microscopy, chondroid chordoma revealed areas that resembled typical chordoma (chordoid areas) and areas that resembled low grade chondrosarcoma (chondroid areas). However, both the chordoid and chondroid areas had an epithelial phenotype and stained strongly for cytokeratin and EMA as well as S-100. 5'-nucleotidase, an enzyme that has been described in chordoma but not in chondrosarcoma, was found in both the chordoid and chondroid areas of one chondroid chordoma. Electron microscopic studies of both the chordoid and chondroid areas in four of the tumors demonstrated both tonofibrils and desmosomes. Chordoma demonstrated immunohistochemical and electron microscopic features that were nearly identical to chondroid chordoma. Chordoma was cytokeratin, EMA, S-100, and 5'-nucleotidase positive. Ultrastructurally, chordoma exhibited variably-sized vacuoles, abundant rough endoplasmic reticulum (RER), and desmosomes with tonofilaments. In contrast to chondroid chordoma, chondrosarcoma consistently stained for only S-100 protein and was cytokeratin, EMA and 5'-nucleotidase negative. Ultrastructurally, chondrosarcoma demonstrated a flocculogranular matrix, glycogen, abundant RER, and scalloped cellular outlines, but lacked desmosomes with tonofilaments. These findings indicate that "chondroid chordoma" is a variant of chordoma with histologic features that may mimic chondrosarcoma. Despite the resemblance of these hyalinized areas to cartilaginous tissue, these tumors retain their epithelial phenotype. Biphasic differentiation is not present. These findings undermine the original premise for distinguishing "chondroid chordoma" from typical chordoma. The authors propose that these tumors be classified as "hyalinized chordomas," rather than "chondroid chordoma," to clarify their histogenesis and avoid confusion with chondrosarcomas of the base of the skull.
Adult↗
Antibody facilitation of multiple sclerosis-like lesions in a nonhuman primate.
In the human disease multiple sclerosis (MS), the immune mechanisms responsible for selective destruction of central nervous system myelin are unknown. In the common marmoset Callithrix jacchus, a unique demyelinating form of experimental allergic encephalomyelitis resembling MS can be induced by immunization with whole myelin. Here we show that the MS-like lesion can be reproduced by immunization against the extracellular domain of a single myelin protein, myelin/oligodendrocyte glycoprotein (MOG). By contrast, immunization against the quantitatively major myelin proteins myelin basic protein or proteolipid protein results in inflammation but little or no demyelination. Furthermore, in the presence of encephalitogenic (e.g., disease-inducing) T cells, the fully demyelinated lesion is reconstructed by systemic administration of IgG purified from whole myelin-, or MOG-immunized animals, and equally by a monoclonal antibody against MOG, but not by control IgG. Encephalitogenic T cells may contribute to the MS-like lesion through disruption of the blood-brain barrier that permits access of demyelinating antibody into the nervous system. The identification of MOG as a major target antigen for autoimmune demyelination in a nonhuman primate should facilitate development of specific immunotherapies for human MS.
Animals↗
Oral sumatriptan in preventing headache recurrence after treatment of migraine attacks with subcutaneous sumatriptan.
Headache recurrence (HR) may occur within 24 hours in approximately 40% of migraine attacks initially treated successfully with 6 mg subcutaneous (SC) sumatriptan. This may be due to the short plasma half-life of sumatriptan. We studied whether an additional dose of 100 mg oral sumatriptan 4 hours after treatment of a migraine attack with 6 mg SC sumatriptan could prevent HR. Patients (n = 667) treated up to three migraine attacks in a randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical trial. For each attack, they initially took open-label 6 mg SC sumatriptan by autoinjector. Four hours later all patients took either 100 mg oral sumatriptan or matched placebo. Patients could take an additional optional oral dose of 100 mg sumatriptan to treat HR. The primary efficacy end point was the number of successfully treated patients without HR within 24 hours after the initial SC injection for the first study attack. Two hundred twenty-five patients were not assessable for HR, mainly because of protocol violations. Of 442 assessable patients, 82/212 in the sumatriptan-treated group (39%) and 89/230 in the placebo-treated group (39%) reported HR in attack 1. Median times to recurrence were 15.6 hours after sumatriptan and 10.3 hours after placebo (p = 0.006). One hundred mg oral sumatriptan taken 4 hours after 6 mg SC sumatriptan does not prevent HR but significantly delays time to recurrence.
Administration, Oral↗
Large effect of age on the survival of patients with glioblastoma treated with radiotherapy and brachytherapy boost.
A retrospective review was undertaken to study the influence of age on the survival of patients undergoing brachytherapy boost for glioblastoma multiforme. From February 1981 through December 1992, 159 adults with primary glioblastoma multiforme underwent high-activity iodine-125 brain implant boost after external beam radiotherapy. There were 98 men and 61 women, ranging in age from 18 to 73 years (median, 52 yr). Karnofsky performance scores ranged from 70 to 100 (median, 90). Surgery before radiotherapy consisted of biopsy in 7% of patients, subtotal resection in 66%, and gross total resection in 27%. External beam radiotherapy doses ranged from 39.6 to 76.8 Gy, with 91% of patients receiving 59.4 to 61.2 Gy. Brachytherapy doses ranged from 35.7 to 66.5 Gy (median, 55.0 Gy) at 0.30 to 0.70 Gy per hour (median, 0.43 Gy/h). Reoperations were performed in 81 patients (51%). Information on quality of life was available for 13 of the 14 living 3-year survivors; 10 patients were steroid independent, and mean Karnofsky performance scores had decreased from 92 at the time of brachytherapy to 75 at the last follow-up. Univariate and multivariate analyses showed that age was the most important parameter influencing survival (P < 0.0005). The nine patients 18 to 29.9 years old had a 3-year survival probability of 78 +/- 14% (median survival was not yet reached at the time of this report), with a follow-up of 145 to 511 weeks in living patients (median, 322 wk).(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Conditional rescue of the dunce learning/memory and female fertility defects with Drosophila or rat transgenes.
Mutations in the Drosophila dunce gene, the structural gene for a cAMP-specific phosphodiesterase (PDE), disrupt normal learning and memory and lead to female sterility. Our experiments address a long-standing question in the genetic dissection of learning and memory of whether dnc is involved in physiological processes underlying learning. Conditional expression of dunce transgenes in dnc adults shortly before training significantly improves learning over nontransgenic controls. Remarkably, behavioral rescue was also observed after induction of a transgene carrying a rat counterpart of dunce. Induction of the transgenes in adult dnc females confers partial rescue of the female sterility phenotype. These data are consistent with a major physiological requirement for the gene's activity in the learning process and show that a rat counterpart can substitute functionally for the Drosophila gene.
3',5'-Cyclic-AMP Phosphodiesterases↗
The use of cranial CT scans in the triage of pediatric patients with mild head injury.
OBJECTIVE: Recent evidence suggests that patients with a normal cranial CT scan after head injury can be safely discharged home from the emergency department. However, supporting data from previous studies has relied on incomplete patient follow-up. We utilized a statewide comprehensive hospital abstract reporting system (CHARS) to assess whether children with normal CT scans after head injury subsequently developed intracranial sequelae in the month following their initial injury. DESIGN: Retrospective case-series study, with comprehensive statewide follow-up for 1 month. SETTING: The emergency department of a Level 1 Trauma Center in Seattle, Washington. PARTICIPANTS: All children (n = 400) with head injury, Glasgow Coma Score of 13 to 15, and initial normal CT scan seen over a 4.5-year time period. All were matched against CHARS to evaluate admissions within 30 days after emergency department disposition. For readmissions, International Classification of Diseases (9th revision) discharge and procedure information was collected. All children were also matched against the state death files. RESULTS: Four children were readmitted for neurologic reasons within 1 month following injury. One child on coumadin for heart disease developed a symptomatic subdural hematoma 5 days after head injury, requiring neurosurgical drainage. One child developed a symptomatic hemorrhagic contusion 3 days after injury, requiring observation only. Two children were readmitted 1 day after injury for concussive symptoms; both were discharged home after observation only. There were no deaths among the study population. CONCLUSIONS: Among children with a normal cranial CT scan after mild head injury, delayed intracranial sequelae requiring intervention are extremely uncommon. In otherwise stable patients, a normal cranial CT scan can identify patients to be safely discharged from the emergency department, and would be more cost-effective than 1 to 2 days of hospital observation.
Adolescent↗
Correlation between the bromodeoxyuridine labeling index and the MIB-1 and Ki-67 proliferating cell indices in cerebral gliomas.
BACKGROUND: Recently, it has been shown that heating paraffin embedded tumor sections in a microwave oven can reactivate an epitope of Ki-67 protein that is recognized by the monoclonal antibody MIB-1. With this technique, a close correlation was shown between the bromodeoxyuridine labeling index (BUdR LI) and the MIB-1 proliferating cell index (PCI) in corresponding regions of glioblastomas. METHODS: The reliability of the MIB-1 PCI as a marker of proliferation was evaluated in 90 cerebral gliomas. The MIB-1 immunostaining of ethanol-fixed, paraffin embedded sections of 23 moderately anaplastic astrocytomas, 22 highly anaplastic astrocytomas, 30 glioblastomas, and 15 mixed malignant gliomas was compared with the BUdR LI and, in some cases, the Ki-67 PCI. RESULTS: MIB-1 positive cells were detected easily in the majority of the cases, and the MIB-1 immunostaining was often superior to that of Ki-67 in individual tumors. The MIB-1 PCI was significantly higher than the Ki-67 PCI and the BUdR LI. Linear-regression analysis showed significant correlations among the three indices. The MIB-1 PCI was correlated with the BUdR LI in each group of the astrocytic tumors and mixed malignant gliomas; the MIB-1 PCI was approximately 2.4-2.8 times higher than the BUdR LI. CONCLUSIONS: The close correlation between the MIB-1 PCI and the in vivo BUdR LI in serial sections of glioma subtypes suggests that MIB-1 immunostaining is a useful technique for analyzing the proliferative potential of individual gliomas.
Adult↗
Two-versus three-sample method for estimating gentamicin pharmacokinetic values.
The performances of two-sample and three-sample methods for estimating gentamicin pharmacokinetic values were studied. The medical records of patients who had received a gentamicin dosage consultation at a Veterans Affairs medical center between June 1989 and May 1991 were reviewed. For each patient, the pharmacokinetics service had prospectively used three serum gentamicin concentrations (SGCs) determined from three blood samples taken during an initial gentamicin regimen to estimate gentamicin pharmacokinetic values and determine the alternative would achieve the desired SGCs. In the two-sample method, the authors retrospectively used the initial peak and trough SGCs determined from two blood samples to estimate pharmacokinetic values and establish an alternative regimen. The two methods were evaluated by comparing their results with each other and with the actual pharmacokinetic values determined from SGCs measured during the subsequent gentamicin regimen. A total of 27 patients (all men; mean age, 62 years) were included in the study. The two-sample and three-sample methods differed significantly in their estimates of elimination rate constant and half-life but not clearance, volume of distribution, or the daily dose needed to achieve the intended SGCs. Neither method produced estimates that differed significantly from the actual pharmacokinetic values. The three-sample method was less biased than the two-sample method in the prediction of trough SGCs. In middle-aged and elderly men, a two-sample method and a three-sample method of estimating gentamicin pharmacokinetics differed significantly only in the prediction of trough SGCs. The difference was probably not clinically important.
Aged↗
Regional differences in bromodeoxyuridine uptake, expression of Ki-67 protein, and nucleolar organizer region counts in glioblastoma multiforme.
To investigate intratumoral differences in indices of tumor cell proliferation, we measured the bromodeoxyuridine labeling index (BrdUrd LI), the Ki-67 protein proliferating cell indices (PCIs) determined by monoclonal antibody MIB 1 in microwave-processed paraffin sections (MIB 1 PCI) and in some cases by monoclonal antibody in frozen sections (Ki-67 PCI), and counts of argyrophilic nucleolar organizer regions (AgNORs) in 20 glioblastomas. In the most actively proliferating areas, MIB 1 and Ki-67 PCIs correlated well with the BrdUrd LI and with each other, while AgNOR counts correlated less strongly with these indices. In less active areas, the MIB 1 PCI and BrdUrd LI changed concomitantly from one area to another within a tumor except in areas of pseudopalisading with necrosis; in these areas the BrdUrd LI decreased significantly compared with neighboring tumor tissue, while the MIB 1 PCI did not. There was very little staining of gemistocytic nuclei with either anti-BrdUrd or MIB 1 monoclonal antibodies; this supports the concept that gemistocytes are mainly quiescent cells. AgNORs in all of the above-mentioned areas varied from tumor to tumor, which suggests that they may indicate some cellular activity other than proliferation. The close correlation between the BrdUrd LI and Ki-67 protein PCIs in corresponding regions of glioblastomas suggests that MIB 1 staining of microwave-processed paraffin sections can be used to evaluate the growth potential of individual glioblastomas and possibly of other gliomas as well.
Adult↗