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Biomedical subjects

R L Davis

Publications and source records attributed to R L Davis.

At least 307 records · Page 17Linked to original sources
PubMed1985

Central nervous system toxicity and cerebrospinal fluid pharmacokinetics of intraventricular 3-[(4-amino-2-methyl-5-pyrimidinyl)ethyl]-1-(2-chloroethyl)-1-nitro soureas and other nitrosoureas in beagles.

The central nervous system toxicity and cerebrospinal fluid (CSF) pharmacokinetics of 3-[(4-amino-2-methyl-5-pyrimidinyl)ethyl]-1-(2-chloroethyl)-1- nitrosoureas, a (ACNU) were determined in beagles and compared to those for three other nitrosoureas, 1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea, 1,3-bis(2-chloroethyl)-1-nitrosourea, and chlorozotocin. Of the four drugs, ACNU was tolerated best and at doses of 0.2 to 0.8 mg/week for 8 consecutive weeks. We found that the average half-time for CSF elimination of ACNU was 18 min (range, 12 to 38 min). This value exceeded the known rate of ACNU decomposition in aqueous solution (28 to 29 min), implying that the disappearance of ACNU from CSF was due to hydrolytic decomposition and cellular entry and/or transcapillary loss across central nervous system capillaries. The drug exposure integral (C X t) of ACNU in the CSF after a "toxic dose low" of 0.8 mg in the dogs would achieve the equivalent of in vitro cell kills in excess of 3 logs for rat 9L and human glioma 126 cells. As a potential therapeutic agent for meningeal neoplasia, the major limiting factor may be that the CSF elimination of ACNU is rapid compared to its equilibration time from ventricle to spinal- and cerebral convexity-subarachnoid space. Based on these results, we have instituted clinical Phase I trials of intra-CSF ACNU.

Animals↗
PubMed1985

Radiation brain damage induced by interstitial 125I sources: a canine model evaluated by quantitative computed tomography.

The canine brain is a good model of the human brain for studying radiation damage after megavoltage x-irradiation for brain tumors. We have further developed this model to study radiation damage induced by high activity interstitial 125I sources. Removable 125I sources were implanted in normal canine brains, and doses of 1,000 to 10,000 rads were delivered to a reference point at a 10-mm radius from the source; dose rates were 35 to 40 rads/hour at the reference point. Serial quantitative analysis of tissue damage (tissue density and contrast enhancement) was done using computed tomographic scanning up to 6 months after implantation and was compared to histopathological findings after the animals were killed. At doses greater than 19,000 rads (i.e., inside the reference point), frank coagulation necrosis was observed. Pronounced vessel-related changes, manifest as areas of contrast enhancement, corresponded to tissues receiving a minimum of 6,000 rads and a maximum of 19,000 rads. These results indicate that this model can be used in serial noninvasive studies to quantify the development of damage induced by interstitial irradiation and to provide dose-response information in individual animals.

Animals↗
PubMed1984

Autopsy findings in the acquired immune deficiency syndrome.

The medical records, premortem biopsy specimens, and autopsy materials from 36 patients with acquired immune deficiency syndrome (AIDS) were reviewed. The majority of the patients were homosexual men. Widely metastatic Kaposi's sarcoma was seen in eight patients, while tumor was confined to the skin in an additional ten. Four patients had high-grade lymphomas. Thirty-five of the 36 patients had at least one opportunistic infection at some point in the course of their illness. Many patients had multiple infectious agents. The most consistent and striking autopsy finding was a severe depletion of lymphoid tissues. Death in the majority (83%) of the patients was attributable to opportunistic infections affecting most commonly the respiratory tract (64%) and meninges (11%). Three patients (9%) died with widely metastatic Kaposi's sarcoma and secondary hemorrhage.

Acquired Immunodeficiency Syndrome↗
PubMed1984

CNS toxicity and CSF pharmacokinetics of intraventricular DFMO and MGBG in beagle dogs.

We have developed a beagle dog model to study the pharmacology and toxicology of anticancer drugs administered through the 3rd or lateral ventricles. A Foltz-type reservoir was implanted SC and connected by tube into a cerebral ventricle. Drugs were administered directly into the reservoir; CSF sampling of drugs administered into the ventricle was achieved directly by tapping the reservoir or by percutaneous puncture of the cisterna magna. In the current study, we evaluated the CSF pharmacokinetics and CNS toxicity of two inhibitors of polyamine metabolism, alpha-difluoromethylornitine (DFMO) and methylglyoxal bisguanylhydrazone (MGBG). Both drugs were judged too toxic to justify intrathecal or intraventricular studies with these agents in patients.

Animals↗
PubMed1984

Analysis of the frequency following response in the cat.

The generators of the frequency following response (FFR) were characterized for three frequency ranges by studying changes in FFR response after lesioning the nuclei within the central brainstem auditory pathway. Responses to low frequency (200-500 Hz) stimulation demonstrated changes in the complexity of the FFR waveform in both time and frequency domains following lesions in the brainstem auditory pathway. The results indicate that the complexity of the low frequency FFR is due to activity from multiple sites within the auditory pathway. The intermediate frequency (700-1500 Hz) responses showed unpredictable amplitude changes following similar lesions and no conclusion could be drawn about the generators of the FFR in this frequency range. The responses to high frequency (3-8 Hz) stimulation showed no reduction in amplitude following serial lesioning. These results, combined with other experimental evidence presented, indicate that the high frequency FFR response originates from the cochlear microphonic. Different electrode configurations were used to evaluate the low frequency FFR. In contrast to multiple generator sources recorded with the standard vertex-mastoid electrode configuration, we were able to record a response contributed primarily by the inferior colliculi with a less peripherally sensitive electrode configuration (vertex-linked-pinnae) at low intensity stimulation. The fact that auditory brainstem nuclei contribute to the FFR in varying amounts depending on the electrode configuration may explain some of the conflicting characterizations of this response in the literature. Despite this difficulty, the FFR neural generators were identified and characterized in the low frequency range using our most sensitive electrode configuration (vertex-mastoid) and in the high frequency range where the single generator is the cochlear microphonic.

Animals↗
PubMed1984

Central nervous system coccidioidomycosis: a clinicopathologic study of treatment with and without amphotericin B.

The clinical and pathologic findings in 32 patients with central nervous system (CNS) coccidioidomycosis were studied. Seventeen patients had received more than 1.5 g of amphotericin B (AMB), chiefly intravenously, during treatment periods of up to eight years. Eight patients had received 246 mg to 1.3 g of AMB, and three patients had received only brief treatment (one to three days; total dose, no more than 100 mg). Fifteen patients had not received AMB. Significant clinical differences between the patients treated with and without AMB were longer survival time following diagnosis of illness (P less than 0.05) and more frequent cranial nerve signs in the treated patients (P = 0.089). The wide spectrum of macroscopic and microscopic lesions in the CNS included meningitis, ventriculitis, hydrocephalus, and cerebritis. Long-standing infections were associated with disseminated discrete foci of gliosis and infarcts in the brain, particularly in the basal ganglia and deep white matter, related to endarteritis obliterans in basilar meninges. In contrast to patients with CNS and systemic mycoses treated with amphotericin B methyl ester (J Infect Dis 146:125, 1982), no diffuse lesions of white matter were found in patients treated with or without AMB. Histopathologic patterns observed in this study included leptomeningitis alone, leptomeningitis with cerebritis, leptomeningitis with cerebritis and infarcts, and the unusual pattern of disseminated miliary granulomas. The frequency and extent of CNS lesions in the groups treated with and without AMB were not significantly different. It is concluded that AMB therapy, while prolonging survival, does not alter the spectrum of pathologic findings in CNS coccidioidomycosis infection.

Adolescent↗
PubMed1984

Bitemporal hypometabolism in Creutzfeldt-Jakob disease measured by positron emission tomography with [18F]-2-fluorodeoxyglucose.

It is well established that Creutzfeldt-Jakob disease (CJD) is caused by a slow infectious agent similar to the scrapie prion. However, the pathogenesis of this infection is poorly understood. Positron emission tomography (PET) was performed on a 54-year-old man with autopsy confirmed CJD using [18F]-2-fluorodeoxyglucose (FDG) and the Donner 280-crystal tomograph. Temporal lobe hypometabolism with hemispheric asymmetry was observed. These findings are similar to those previously obtained in PET-FDG studies of patients with clinically defined Alzheimer disease (AD). The similarities in the regional metabolic alterations between CJD and AD provide additional evidence for the possibility that AD may be caused by a slow infectious prion.

Autopsy↗
PubMed1984

Only site-directed antibodies reactive with the highly conserved src-homologous region of the v-abl protein neutralize kinase activity.

Antisera specific for six regions of the v- abl protein were used to serologically characterize the Abelson murine leukemia virus tyrosine kinase. Chemically synthesized peptides corresponding to the predicted v- abl protein sequence and larger regions of the v- abl protein expressed as fusion proteins in bacteria were used as immunogens. The specificity of each antiserum was confirmed by immunoprecipitation analysis with defined deletion mutants of Abelson murine leukemia virus. Several of these v- abl -specific antisera display much higher titers and avidities than serum harvested from mice bearing Abelson murine leukemia virus-induced tumors, previously the only source of anti- abl -specific serum. Two antisera were found to block the in vitro autophosphorylation of the v- abl protein as well as its ability to phosphorylate a peptide substrate. Examination of the sites against which the kinase-blocking antisera were prepared revealed that both are in close proximity to the in vivo sites of tyrosine phosphorylation, which fall within the region of high homology with v-src and other tyrosine kinases. Antisera directed against other regions of v- abl did not inhibit kinase activity.

Abelson murine leukemia virus↗
PubMed1984

Isolation of the Drosophila melanogaster dunce chromosomal region and recombinational mapping of dunce sequences with restriction site polymorphisms as genetic markers.

Using the method of chromosomal walking, we have isolated a contiguous region of the Drosophila melanogaster X chromosome which corresponds to salivary gland chromosome bands 3C12 to 3D4. This five-band region contains approximately 100 kilobases of DNA, including those sequences comprising dunce, a gene which functions in memory and cyclic nucleotide metabolism. Genome blots of DNA from flies carrying several different chromosomal aberrations with breakpoints in the region have been probed with the isolated clones to map the breakpoints on the cloned DNA and to delimit dunce sequences. This has localized dunce to a 50-kilobase region. In addition, we have searched this 50-kilobase region for restriction site polymorphisms between X chromosomes from different Drosophila strains by genome blotting experiments, and we have followed the segregation of detected polymorphisms and dunce alleles after meiotic recombination. The data map one dunce mutation between two polymorphisms located 10 to 12 kilobases apart.

Animals↗
PubMed1984

Effect of microsurgical and carbon dioxide and argon laser resection on recurrence of the intracerebral 9L rat gliosarcoma.

The intracerebral 9L rat brain tumor was resected from 38 rats with the use of standard microsurgical techniques, the carbon dioxide laser, or the argon laser. The extent of resection was evaluated by histological examination, and the effect on survival of the three methods was compared. All three methods achieved histologically verifiable gross total resection, and tumor recurrence after resection by all three methods occurred at the same rate.

Animals↗
PubMed1984

Supratentorial malignant gliomas of childhood. Results of treatment with radiation therapy and chemotherapy.

Twenty-seven patients aged 1 to 18 years harboring supratentorial (20 in the cerebrum and seven in the thalamus) malignant gliomas were treated between 1975 and 1982. There were four glioblastomas multiforme, 14 anaplastic astrocytomas, and nine malignant gliomas. All patients had a subtotal resection or biopsy as the initial procedure and received postoperative radiation therapy (RT). Fifteen of 27 patients were treated by RT alone; 14 had tumor progression with a median time to tumor progression (MTP) of 65 weeks. Twelve patients were treated with chemotherapy as an adjuvant to RT; only seven had tumor recurrence, with an MTP of 130 weeks. Of the 21 patients with recurrent tumors in both groups, 18 were treated with chemotherapy alone, or chemotherapy with a second surgical procedure or second course of RT. For all histological grades of tumor, the MTP for first recurrence was 75 weeks and the median survival time was 180 weeks. Age at initial diagnosis was found to be a statistically significant prognostic factor, with patients younger than 10 years of age surviving longer than patients aged over 10 years (p = 0.02).

Adolescent↗
PubMed1984

Distribution of hematoporphyrin derivative in the rat 9l gliosarcoma brain tumor analyzed by digital video fluorescence microscopy.

A digital video fluorescence microscopy technique was used to evaluate the distribution of hematoporphyrin derivative (HPD) in the rat intracerebral 9L gliosarcoma brain-tumor model at 4, 24, 48, and 72 hours after intravenous administration of 10 mg/kg of the drug. Compared to surrounding normal brain, there was significant preferential uptake of HPD into the tumor. In sections surveyed, fluorescence reached a maximum value by 24 hours; however, only 33% to 44% of the tumor was fluorescent. In contrast, fluorescence within the surrounding normal brain was maximum at 4 hours, but was present in less than 1% of the brain tissue evaluated. The effect of HPD sensitization to a laser light dose (633 nm) of 30 joules/sq cm delivered through the intact skull was evaluated histologically in 10 rats. A patchy coagulation necrosis, possibly corresponding to the distribution of HPD fluorescence seen within the tumor, was observed. There was evidence that photoradiation therapy (PRT) affects defective tumor vasculature and that a direct tumor cell toxicity spared normal brain tissue. Despite these findings, limited uptake of HPD in tumor and the brain adjacent to tumor may decrease the effectiveness of PRT in the 9L gliosarcoma brain-tumor model. Because of the similarity between the capillary system of the 9L tumor and human brain tumors, PRT may have a limited therapeutic effect in patients with malignant brain tumors.

Animals↗
PubMed1984

Computed tomography analysis of the canine brain: effects of hemibrain X irradiation.

Radiation damage induced by megavoltage X irradiation in normal brain tissue can manifest as one of several pathologic processes depending upon the time of brain examination after irradiation. Serial quantitative computed tomography (QCT) analyses were used to study the development of radiation damage in the normal canine brain. Tissue density, volume of low density areas, magnitude and volume of contrast uptake, and ventricular volume were measured following hemibrain irradiation and were correlated with histopathology. Low density areas correlated with edema, demyelination, axonal swelling, and necrosis and appeared 3-4 months after irradiation. Large regions of contrast enhancement (coagulation necrosis and associated vascular changes) appeared 5-6 months after irradiation. Results from this study demonstrated that the pathologic changes induced in the dog brain after single doses of X rays were similar to the changes observed in nonhuman primates and man after exposure to radiation.

Animals↗
PubMed1983

Pediatric brain stem tumors: radiographic, pathological, and clinical correlations.

A retrospective analysis of the case histories of 21 pediatric patients (ages, 2.5 to 18 years) with a histologically proven diagnosis of brain stem glioma was performed to determine whether patterns of radiographic appearance could be correlated with pathology. Based on the computed tomographic or pneumoencephalographic appearance of the tumor at the time of clinical diagnosis, tumors were divided into four types: central intrinsic (Type I), central exophytic expansion into the 4th ventricle (Type II), eccentric exophytic expansion not involving the 4th ventricle (Type III), and both eccentric and central exophytic expansion (Type IV). Regardless of the radiographic classification, all patients except one, who harbored a well-differentiated astrocytoma in the area of the pons, had an anaplastic astrocytoma (n = 14) or a glioblastoma multiforme (n = 6). There was no appreciable difference in survival between patients with either tumor histology. The presence of a cystic component did not affect survival. High resolution computed tomographic scans, with reconstructed images of the posterior fossa, can predict the presence and location of brain stem tumors and associated cysts and probably the histological nature of the tumor.

Adolescent↗