Relationship among prognostic laboratory indices in breast cancers.
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Biomedical subjects
Publications and source records attributed to J M Miller.
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Kynurenic acid (KYA) is the only known endogenous excitatory amino acid antagonist in mammalian brain. In the present study we examined the effects of precursor loading with kynurenine (KYN) and blockade of organic acid transport with probenecid, either alone or in combination, on extracellular striatal KYA concentrations in unanesthetized rats. Baseline KYA concentrations were 1.61 +/- 0.29 pmol/ml. Following administration of KYN 150 mg/kg with increasing doses of probenecid a maximal increase in KYA to 946 +/- 210 pmol/ml was seen with probenecid 200 mg/kg. Probenecid 200 mg/kg alone increased KYA levels to 16.0 +/- 5.2 pmol/ml. The combination of probenecid 200 mg/kg with KYN 450 mg/kg produced a maximal increase of KYA to 2085 +/- 391 pmol/ml, a 1300-fold increase indicating marked potentiation. These results show that pharmacologic manipulation can markedly increase extracellular fluid concentrations of KYA into a range which may be useful in attempts to block NMDA receptor-mediated neurotoxicity.
Nerve fiber layer height measured with respect to a standardized retinal reference plane is diminished by glaucoma. The definition of the reference plane influences the nerve fiber layer measurements. We empirically determined the best reference plane for measurement of nerve fiber layer height. Optimal parameters for measurement reproducibility were determined for a group of 6 normal and 6 glaucomatous eyes each imaged nine times. Optimal ability to distinguish normal from glaucomatous eyes was determined for a group of 33 normal eyes and 36 glaucomatous eyes each imaged once. Measurements with the smallest variability (root mean square error = 32 microns) and the highest sensitivity (83%) and specificity (88%) were achieved when the reference plane is defined by portions of the image from a peripheral temporal area 32 degrees wide, and for two peripheral nasal areas of 55 degrees width centered 30 degrees above and below horizontal. These parameters for the definition of the reference plane should provide measurements of nerve fiber layer height with the least variability and the greatest ability to discriminate between eyes with early glaucomatous damage and normal eyes.
A bovine herpesvirus 1 (BHV 1) mutant variant with a deletion in the thymidine kinase (TK) gene was assessed for its ability to establish latency and be reactivated in cattle. After treatment with dexamethasone, reactivated TK- BHV 1 was isolated from one of four cattle that received virus by intravenous inoculation only, and from four of four cattle that received virus by intranasal, intravaginal, and intravenous inoculation. Results prove that TK- BHV 1 will establish latency and can be reactivated in the natural host.
OBJECTIVE: Because poor fetal growth is a significant cause of perinatal morbidity and mortality, a prospective study was undertaken to evaluate the ability of real-time ultrasonography and Doppler velocimetry to detect the small-for-gestational-age fetus. STUDY DESIGN: A prospective study of 136 women at risk for fetal growth abnormalities was conducted. Patients were delivered within 3 weeks and had live-born, nonanomalous, singleton infants. The relative estimated fetal weight (estimated fetal weight divided by the median birth weight for gestational age) and the systolic/diastolic ratio were measured and compared with receiver-operator characteristic curves. In this method the area under the curve is the index of performance. RESULTS: Forty-six infants were small for gestational age. Although both relative estimated fetal weight (area under the curve = 0.923) and systolic/diastolic ratio (area under the curve = 0.837) were significantly associated with the small for gestational age fetus, the former was more strongly correlated, p = 0.021. CONCLUSION: Relative estimated weight is more sensitive and specific and should be the preferred parameter when gestational age is known.
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We describe an extraocular muscle (EOM) force transducer that provides low-noise signals from an alert animal for several months, is implanted without disinserting the muscle, and is well-tolerated by the body, and present results obtained with the device. The transducer can be used to study orbital statics and dynamics, and oculomotor control signals undiminished by orbital low-pass filtering and antagonistic pairing of muscles. It may provide an index of effective EOM innervation, useful in studies of orbital tissue healing and plasticity, and oculomotor (OM) signal adaptation. During horizontal saccades transducers implanted in the lateral rectus (LR) and medial rectus (MR) of a monkey trained to fixate revealed an agonist muscle tension waveform corresponding to the "pulse-slide-step" pattern of saccadic innervation, and an antagonist waveform that was similar within a scale factor. We never observed transient increases in antagonist force at the ends of saccades (active braking) or at the beginnings. Onset of saccadic force in LR preceded that in MR by 1.6 msec for abducting saccades, and lagged that in MR by 1.1 msec for adducting saccades. During vertical saccades, transient force changes were found in LR and MR, which were likely due, at least in part, to globe translation. LR and MR forces during fixation tended to be largest with the eye about 10 degrees in elevation, and smallest in depression, indicating that effective total innervation was a function of vertical gaze, or that there was variation in the elastic component of muscle force related to orbital geometry, with LR and MR innervation independent of vertical gaze. An exponential decrease in fixation force, having a time constant of about 10 days, was observed after implantation. This may have reflected adaptive muscle lengthening or post-surgical healing.
The effect of vehicle and occlusion on the in vitro percutaneous absorption of [methylene-14C]-benzyl acetate (1.7-16.6 mg/cm2) has been studied in diffusion cells using full thickness skin from male Fischer 344 rats. Absorption of neat benzyl acetate through rat skin occluded with parafilm was 49.3 +/- 2.0% (mean +/- SD, n = 4) after 48 hr. When benzyl acetate in ethanol was applied to the skin and the skin was occluded with parafilm, the extent of absorption at 48 hr was not significantly different from that after neat application. However at 6 hr, as the ethanol content of the application mixture was increased, the absorption of benzyl acetate through occluded skin was enhanced proportionally (r = 0.999). When phenylethanol was used as a vehicle, the extent of the benzyl acetate absorption through occluded skin at 48 hr was enhanced (P less than 0.05) compared with that after application neat; with 50% (v/v) phenyl-ethanol, absorption at 48 hr was 56.3 +/- 4.9%. However, this enhanced absorption did not correlate with the proportion of phenylethanol in the application mixture. When dimethylsulphoxide was used as a vehicle, the extent of absorption of benzyl acetate through occluded skin at 48 hr was enhanced (P less than 0.05) compared with that after application neat (absorption was 59.3 +/- 3.7% of the applied dose when 50% (v/v) dimethylsulphoxide was used). As the dimethylsulphoxide content of the application mixture was increased, the absorption of benzyl acetate was enhanced proportionally. Occlusion of the skin surface with parafilm often significantly enhanced absorption (P less than 0.05), although the effect varied with time and vehicle. In general, the degree of any enhanced absorption caused by the use of a vehicle or occlusion of the skin was small, and, in most cases, would be unlikely to be toxicologically significant.
Reduced cochlear blood flow (CBF) has been implicated in various pathologies of the inner ear, including sudden deafness, noise-induced hearing loss and Meniere's disease. Thus the aim of some current therapeutic regimens to treat these conditions is to increase CBF and thereby improve oxygenation of the inner ear tissues. Most of the vasodilating agents in clinical use, however, do not have specific experimental evidence to support their effects on CBF. The hypotension which can follow systemic administration may limit their local effectiveness and general utility, just as it complicates the interpretation of the data in animal experiments. In the current study we investigated the effect of six agents, known for their systemic cardiovascular actions, on CBF: hydralazine, sodium nitroprusside, papaverine, nicotinic acid, verapamil and histamine. The effect of these drugs was studied after topical applications on the round window membrane (RWM) and systemic intravenous administrations. CBF was monitored with a laser Doppler flowmeter (LDF). Topical administration of sodium nitroprusside was the most effective in increasing CBF, followed, in order, by hydralazine and histamine. No change in CBF was observed for papaverine, verapamil or nicotinic acid. Systemic administrations of all the agents caused a marked decrease in blood pressure and variable effects on CBF. We discuss the CBF changes in relation to the different pharmacological mechanisms of action of each drug. The study demonstrates the effectiveness of topical application of vasodilating agents in increasing CBF.
Cochlear implants are being applied to an ever widening patient population, including children in whom lifetime use of these devices is anticipated. Replacement of implants can be expected for reasons of device failure as well as future upgrading. This investigation was undertaken to examine the effect of cochlear electrode explanation and reimplantation on spiral ganglion cell survival. Guinea pigs with normal ears were initially implanted and either explanted or explanted and reimplanted (at 2 months) with a single wire ball-tip intracochlear electrode or a silastic carrier (each remaining for an additional 2 months). Little loss of hair cells or auditory nerve was observed across experimental groups and normal controls. Restricted basal turn cochlear and spiral ganglion cell loss was observed in a few animals in each group and was likely associated with mechanical damage from initial implantation. Likewise the scattered organ of Corti damage and hair cell loss observed was noted in only a few cochleae in each experimental group. Therefore, no significant differences in the average pathology across experimental groups and controls were observed. Thus, explantation or explantation with subsequent reimplantation does not appear to constitute an additional significant pathological risk compared to implantation alone.
Using intravital microscopy, we observed both decreases in red blood cell velocity and possible vasoconstriction in stria vascularis capillaries of the rat cochlea in response to loud sound (Quirk et al., 1991). However, our observation of vasoconstriction was subject to error in measurements from the two dimensional images obtained with our silicon intensified (SIT) camera due to the influence of focus causing image blur. The purpose of the current study was to apply an extended focus microscopy technique to obtain quantitative assessment of vessel diameter changes (Avinash et al., 1992), as well as to extend these studies to the guinea pig model. Broad-band sound stimulation at intensities of 84 dB SPL and 110 dB SPL were used. The results show that loud sound induces a sequence of changes in cochlear blood flow. Stimulation with 110 dB SPL resulted in a mean increase (maximum = 27%) in red blood cell velocity for the first 20 min of exposure followed by a gradual decrease below baseline (minimum = -12%) prior to termination of the signal. This velocity decrease and subsequent recovery were associated with significant changes in vessel diameters of selected and measured capillaries. In contrast, the 84 dB SPL stimulus caused an increase in red blood cell velocity (maximum = 20%) and vessel diameter (mean = 7.5) during the stimulation period. No recovery was observed during the 10 min observation period following sound. Several possible mechanisms responsible for these changes are discussed.
Since its development in 1988, a serologic typing scheme for Xanthomonas maltophilia, based on 31 O antigens, has been successfully used to serotype isolates involved in nosocomial outbreaks in the United States. To determine if this serotyping scheme would be useful in typing X. maltophilia isolates from world-wide sources, we obtained additional isolates from 10 countries; of 900 isolates tested, 795 (88.3%) were typable. In order of predominance, the three most common serotypes were 10, 3 and 19. These three serotypes were most frequently associated with respiratory and blood isolates. This serotyping system is useful as an epidemiologic screening method for universal typing of outbreaks of X. maltophilia infections.
OBJECTIVE: To determine risk factors for and modes of transmission of Xanthomonas maltophilia infection/colonization. DESIGN: Surveillance and cohort study. SETTING: A 470-bed tertiary trauma-referral community hospital. PATIENTS: From January 1, 1988 to March 17, 1989, 106 intensive care unit patients developed X maltophilia infection/colonization. We defined a case as any intensive care unit patient who, from July 15, 1988, through March 17, 1989 (epidemic period), had X maltophilia infection/colonization greater than or equal to 48 hours after intensive care unit admission. We identified 45 case patients and 103 control patients (persons in the shock-trauma intensive care unit for greater than or equal to 72 hours during the epidemic period who had no X maltophilia-positive culture). RESULTS: Cases were significantly more likely to occur in the shock-trauma intensive care unit than in all other intensive care units combined. Mechanical ventilation, tracheostomy, being transported to the hospital by airplane, and receipt of a higher mean number of antimicrobials were risk factors for X maltophilia infection/colonization. Risk of X maltophilia infection/colonization was significantly greater among cases exposed to a patient with a X maltophilia surgical wound infection than among those without such exposure (relative risk = 1.3, p = .03). Animate and inanimate cultures revealed X maltophilia contamination of the hospital room of a patient with an X maltophilia surgical wound infection, of respiratory therapy equipment in this patient's room, of respirometers shared between patients, and of shock-trauma intensive care unit personnel's hands. Related environmental and clinical isolates were serotype 10. CONCLUSIONS: Mechanically ventilated patients receiving antimicrobials in the shock-trauma intensive care unit were at increased risk of X maltophilia infection/colonization. Patients with draining X maltophilia surgical wound infections served as reservoirs for X maltophilia, and contamination of the respirometers and the hands of shock-trauma intensive care unit personnel resulted in patient-to-patient transmission of X maltophilia.
The effects of 1-methyl-4-phenylpyridinium (MPP+) were studied in rat striatum. Using freeze-clamp, microwave, and water-suppressed proton chemical shift magnetic resonance imaging techniques, MPP+ resulted in marked increases in lactate and a depletion of ATP for up to 48 h after the injections. MPP+ produced dose-dependent depletions of dopamine, serotonin, gamma-aminobutyric acid, and substance P that were partially blocked at 1 week by prior decortication or completely blocked by MK-801 at 24 h. The lesions showed relative sparing of somatostatin-neuropeptide Y neurons, consistent with N-methyl-D-aspartate (NMDA) excitotoxicity. MPP+ produces impairment of oxidative phosphorylation in vivo, which may result in membrane depolarization with persistent activation of NMDA receptors and excitotoxic neuronal degeneration. An impairment of energy metabolism may therefore underlie slow excitotoxic neuronal death in neurodegenerative diseases.
The API 20E bacterial identification system has been used for 19 years, often as the standard with which other identification systems are compared. Because the accuracy of this system compared with conventional biochemical tests has not been determined in many years, we evaluated the API 20E linear strip by using 291 typical and atypical strains of the family Enterobacteriaceae taken from a culture collection. At 24 h, the API 20E correctly identified by genus and species 229 of 291 (78.7%) of the strains, using Salmonella and Shigella serotyping where indicated. At 48 h, 95.2% were correctly identified by using additional biochemical tests as recommended by the manufacturer. The API 20E misidentified eight (2.7%) strains; these strains were not limited to any particular genus. When 81 of these Enterobacteriaceae strains were arranged into a weighted assortment correlating to the frequency with which they might be found in a clinical laboratory, the API 20E correctly identified 71 (87.7%) at 24 h and 78 (96.3%) at 48 h. This evaluation concluded that the accuracy of the identification of Enterobacteriaceae strains at 24 h (78.7%) may be significantly lower than that of earlier evaluations. However, there is no significant difference in the ability of the API 20E to correctly identify "challenge" type organisms (229 of 291) versus routine hospital isolates (71 of 81) (P greater than 0.05), but the system is not as accurate as the conventional biochemical method of identification.
The bovine lentivirus, known as bovine immunodeficiency-like virus (BIV), is genetically, structurally, and antigenically related to human immunodeficiency virus type 1 (HIV-1). It is not known whether sera from persons exposed to BIV proteins would show either positive or indeterminate reactivity on HIV-1 antibody tests. We used a BIV Western blot (immunoblot) analysis to examine human sera characterized as HIV-1 antibody positive, HIV-1 antibody negative, HIV-1 persistently indeterminate, HIV-1 p17 antibody positive only, HIV-1 p24 antibody positive only, human T-cell leukemia virus type 1 (HTLV-1) p19 antibody positive only, or HTLV-1 p24 antibody positive only. None of these sera were positive by Western blot to BIV-specific proteins. Many of these sera, however, displayed strong reactivities to bovine cell culture antigens on blots prepared from both mock-infected and BIV-infected cell cultures. The HIV-1 p17 and p24 antibody-positive and the HTLV-1 p19 and p24 antibody-positive sera were further examined by Western blot to bovine leukemia virus (BLV) and were found to be negative. We examined sera from laboratory personnel at risk for BIV exposure, including two laboratory workers who were exposed to BIV by accidental injection with BIV-infected cell culture material, and found no evidence of seroconversion to BIV-specific proteins. We tested 371 samples of fetal bovine sera, each sample representing serum pooled from one to three fetuses. All samples were negative by BIV Western blot. To date, we have not detected any human sera with antibody to BIV-specific proteins. Our data indicate that persistently indeterminate results on HIV-1 Western blot are not caused by a human antibody response to BIV proteins.
We evaluated the ability of the Baxter autoSCAN-W/A System (MicroScan Division, Baxter Diagnostics, Inc., West Sacramento, Calif.) to use the rapid (2-h) gram-negative identification panel for accurate identification of members of the family Enterobacteriaceae. At 2 h, 353 of 467 (75.6%) strains in a challenge set of biochemically typical and atypical stock cultures were correctly identified to genus and species. Another 76 (16.3%) strains were correctly identified to genus and species after the performance of recommended additional biochemical testing. Thus, at 24 h, 91.9% of the 467 strains were correctly identified. Twenty-two strains (4.7%) were identified to the correct genus but the incorrect species, and 16 strains (3.4%) were misidentified. Of these 16 strains, 9 were incorrect at 2 h, and 7 were incorrect after the additional testing. Because the system is based on fluorogenic substrates, no conventional tests were readily available with which to compare aberrant reactions. These results suggest that the autoSCAN-W/A with its rapid gram-negative panels is acceptable for the identification of the Enterobacteriaceae in a clinical microbiology laboratory.
The early pathogenic effects of bovine immunodeficiency-like virus (BIV) were studied in calves experimentally inoculated with BIV. All animals inoculated with BIV R29-infected cells seroconverted by 6 weeks postinoculation, and BIV was recoverable from each animal at 2 weeks postinoculation. However, levels of BIV replication in vivo appeared to be low. In situ hybridization studies indicated that during peak periods of viral replication in vivo, less than 0.03% of peripheral blood mononuclear cells were expressing detectable levels of viral RNA. Moreover, the levels of viral RNA in these cells in vivo were less than 1/10 the levels observed in persistently infected cells in vitro. BIV-inoculated calves had significantly higher numbers of circulating lymphocytes, and follicular hyperplasia was observed in lymph nodes, hemal nodes, and spleen. The histopathological changes observed in BIV-infected calves were similar to changes found early after infection with the immunosuppressive lentiviruses, including human immunodeficiency virus type 1.