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Biomedical subjects

R L Davis

Publications and source records attributed to R L Davis.

At least 73 records · Page 4Linked to original sources
PubMed1999

4-Alkyl- and 3,4-dialkyl-1,2,3,4-tetrahydro-8-pyridono[5,6-g]quinolines: potent, nonsteroidal androgen receptor agonists.

A series of human androgen receptor (hAR) agonists based on 4-alkyl-; 4,4-dialkyl-; and 3,4-dialkyl-1,2,3,4-tetrahydro-8-pyridono[5,6-g]quinoline was synthesized and evaluated in competitive receptor binding assays and an androgen receptor cotransfection assay in a mammalian cell background. A number of compounds in this series demonstrated activity equal to or better than dihydrotestosterone in both assays and represent a novel class of compounds for use in androgen replacement therapy.

Androgens↗
PubMed1999

Cyclic AMP phosphodiesterases are localized in regions of the mouse brain associated with reinforcement, movement, and affect.

Four cyclic AMP-specific, rolipram-inhibited phosphodiesterases (PDE4s) have been identified in mammals; all four are homologs of dunce, a gene required for learning and memory in Drosophila. To determine the distribution of PDE4s in the mammalian brain, specific antibodies were generated against the proteins encoded by each of three dunce homologs PDE4A, PDE4B, and PDE4D in the mouse. On Western blots, these antibodies recognized multiple protein species in all brain regions studied. Immunohistochemical studies showed that both cell bodies and neuropil were well labeled in selected regions throughout the brain. Immunoreactivity for PDE4A was found predominantly in the anterior olfactory nucleus, subiculum, layer V pyramidal neurons from the cerebral cortex, and corticospinal tracts. By contrast, anti-PDE4B-labeled neurons were observed in the inferior olive, the paraventricular and supraoptic nuclei of the hypothalamus, and in the ventral striatum. Regions of neuropil containing high levels of PDE4B immunoreactivity included the cerebellar molecular layer, globus pallidus, nucleus accumbens, and substantia nigra. Anti-PDE4D antibody distinctly labeled cerebellar Purkinje cells as well as neurons in the medial habenula and thalamic nuclei. Fibers in the fasciculus retroflexus, interpeduncular nuclei, and periaqueductal gray were also stained with this antibody. These findings indicate that the distribution of PDE4s in the brain is remarkably segregated, and suggest that each of these enzymes has a unique functional role. Furthermore, the data support the notion that rolipram, the PDE4-specific inhibitor that acts as an antidepressant in humans, may mediate its behavioral effects through PDE4B, which is highly localized to neural pathways known to underlie reward and affect in mammals.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1999

Final report on the University of California-San Francisco experience with bromodeoxyuridine labeling index as a prognostic factor for the survival of glioma patients.

BACKGROUND: At the University of California-San Francisco (UCSF), a labeling index (LI) based on in vivo administration of bromodeoxyuridine (BUdR) was routinely determined in tumors from patients with infiltrating gliomas for the 10-year period, 1984-1994. Considered an indicator of tumor proliferative potential, it was anticipated that the BUdR LI would aid in determining patient prognosis. The data have now matured, and a final report on the extensive UCSF experience is appropriate. METHODS: Patients were grouped separately based on tumor grade and whether LI was determined at the time of primary diagnosis or at recurrence. To assure data quality and consistent follow-up, only adult patients entered on clinical trials were included. Patients with primary Grade 2 gliomas could not be included because most of these patients did not enter clinical trials. Each patient LI was categorized as low (lowest quartile), moderate (between the 25th and 75th percentiles), or high (highest quartile). Statistical analyses included log rank and multivariate proportional hazards models. RESULTS: One hundred ninety patients with primary tumors (69 Grade 3, 121 Grade 4) and 149 patients with recurrent tumors (24 Grade 2, 37 Grade 3, and 88 Grade 4) were included. LI score was predictive of survival (P < or = 0.02 for univariate or multivariate analyses) in all but the primary Grade 4 patients. For that group, it was a significant predictor (P = 0.03) only among those surviving > or = 1.5 years. CONCLUSIONS: BUdR LI improved the predictability of long term patient outcome both initially and at the time of recurrence. Further research on measures of tumor proliferative potential as markers of outcome is warranted.

Adolescent↗
PubMed1999

Early newborn hospital discharge and readmission for mild and severe jaundice.

OBJECTIVES: To further explore the relationship of early newborn hospital discharge and readmission for jaundice, and to determine if early hospital discharge was associated with increased severity of jaundice among those readmitted. METHODS: We performed a population-based case-control study using Washington State vital statistics, birth certificates, and hospital discharge abstracts from 1991 to 1995. Cases included 750 infants readmitted to the hospital for jaundice in the first 2 weeks of life; controls included 3192 infants not readmitted. Infants with severe medical conditions and those delivered by cesarean section were excluded. Early hospital discharge was defined as fewer than 30 hours in the hospital, late hospital discharge, 30 to 78 hours. We assessed the risk for hospital readmission for jaundice, for hospital readmissions classified as brief (< or =2 days) or prolonged (>2 days), and for hospital readmissions classified as uncomplicated or complicated. RESULTS: Infants discharged from the hospital early were at increased risk for jaundice (odds ratio, 1.34 [95% confidence interval, 1.10-1.64] adjusted for birth year, gestational age, maternal race and age, parity, payer, and infant sex). The risk associated with early hospital discharge was similar regardless of whether the hospital readmission was brief or prolonged and complicated or uncomplicated. One hundred twenty-two infants would have to stay for longer than 30 hours to avoid 1 jaundice readmission. CONCLUSIONS: While newborns discharged from the hospital early are at increased risk for hospital readmission for jaundice, the clinical significance is limited. Mandating longer neonatal stays may not be the most effective strategy to prevent hospital readmission for jaundice and its complications.

Case-Control Studies↗
PubMed1999

Cryptic Mucor infection leading to massive cerebral infarction at initiation of antileukemic chemotherapy.

A 74-year-old man with newly diagnosed acute myelogenous leukemia unexpectedly suffered a massive cerebral infarct on day 2 of induction chemotherapy. Clinically, the hemorrhagic infarct was thought to be due to leukostasis and thrombocytopenia. Necropsy, however, revealed that Zygomycetes-type hyphae had infiltrated cerebral vessels in and near the infarct. The fungal infection was clinically silent otherwise, although fungal elements were also identified in the lung at autopsy. This case illustrates how closely fungal infection may resemble a leukemia-associated cerebrovascular accident.

Aged↗
PubMed1999

Pregnancy and perinatal outcomes in migraineurs using sumatriptan: a prospective study.

BACKGROUND: Sumatriptan is an acute treatment for migraine which is often used by women in their child-bearing years, and who become unexpectedly pregnant. Within the context of the post-marketing use of sumatriptan injection for the acute treatment of migraine, and in compliance with approved labeling, we wished to compare perinatal pregnancy outcomes in women who did and did not use the drug after conception. METHODS: Open-label, prospective study conducted in 12,339 migraineurs (including 9,861 women) whose demography and consumption pattern of sumatriptan injections were typical, and were predicted to include 150 pregnancies. Outcome of pregnancy was the end-point. RESULTS: There were 168 of 173 pregnancies that were well-documented. Sumatriptan was only used prior to conception in 92 cases. There were 76 first trimester exposures to sumatriptan. There were no differences in pregnancy outcome between the two groups. CONCLUSIONS: Perinatal and pregnancy outcome did not differ between patients who had and had not used sumatriptan after conception, at the resolution of these sample sizes. This study design complements the ongoing pregnancy registry, which is now widened to patients exposed to all formulations of sumatriptan.

Abortion, Spontaneous↗
PubMed1999

Familial encephalopathy with neuroserpin inclusion bodies.

We report on a new familial neurodegenerative disease with associated dementia that has presented clinically in the fifth decade, in both genders, and in each of several generations of a large family from New York State-a pattern of inheritance consistent with an autosomal dominant mode of transmission. A key pathological finding is the presence of neuronal inclusion bodies distributed throughout the gray matter of the cerebral cortex and in certain subcortical nuclei. These inclusions are distinct from any described previously and henceforth are identified as Collins bodies. The Collins bodies can be isolated by simple biochemical procedures and have a surprisingly simple composition; neuroserpin (a serine protease inhibitor) is their predominant component. An affinity-purified antibody against neuroserpin specifically labels the Collins bodies, confirming their chemical composition. Therefore, we propose a new disease entity-familial encephalopathy with neuroserpin inclusion bodies (FENIB). The conclusion that FENIB is a previously unrecognized neurodegenerative disease is supported by finding Collins bodies in a small kindred from Oregon with familial dementia who are unrelated to the New York family. The autosomal dominant inheritance strongly suggests that FENIB is caused by mutations in the neuroserpin gene, resulting in intracellular accumulation of the mutant protein.

Amino Acid Sequence↗
PubMed1999

Differentiation of cyst-forming stria vascularis tissues in vitro.

The marginal cells of the stria vascularis possess distinctive morphological characteristics associated with their role in endolymph production. Interestingly, when stria-derived epithelial cells are grown in association with the underlying mesenchyme, the final differentiation of these cell types does not occur. Beyond the rudimentary polarity that is established, similar to that shown in epithelial monolayers, cells in culture bear only a slight resemblance to their marginal cell counterparts in vivo. The ultrastructural features that typify these epithelia, extensive cytoplasmic invaginations, with an abundance of mitochondria, and darkly stained cytoplasm, are not evident under standard culture conditions. In order to determine whether fluid transport, a key function of the stria vascularis, has an effect on the ultrastructural morphology, we examined de novo stria vascularis tissues that formed a fluid-filled cyst in vitro. We found that only cells associated with the luminal structure demonstrated dark cytoplasmic staining and amplification of the basolateral membrane of the marginal cells. Additionally, other epithelial features, such as mitochondria-rich and microvilli-rich cells, were observed in cyst-forming tissues. The enhancement of the marginal cell specializations was not as robust as that observed in vivo; however, they were clearly more extensive when compared to cells in the same culture that were not associated with a fluid-filled lumen. Thus it appears that fluid transport may be necessary to maximize differentiation of stria vascularis tissues in vitro.

Animals↗
PubMed1999

Prospective large-scale study of the tolerability of subcutaneous sumatriptan injection for acute treatment of migraine.

To investigate prospectively serious adverse events associated with sumatriptan injection, we studied 12,339 typical migraineurs for up to 12 months each. This study imitated the ordinary clinical use of sumatriptan injection except that: (a) a short, written informed consent was required, (b) there was a centralized, automated dispensing service that audited each patient's product use, (c) patients were sometimes reviewed by telephone, and (d) drug supply and medical consultation were without charge. All adverse events were recorded regardless of etiology. There were 25 fatalities during the study, none being attributable to sumatriptan injection. Of six strokes in the study, two occurred soon after treatment of a migraine attack with sumatriptan injection; whether these were migraine-related or drug-related is discussed. None of the three myocardial infarctions was due to sumatriptan injection use. We conclude that sumatriptan injection is well tolerated when used in accordance with labeling.

Adolescent↗
PubMed1999

Migraine polypharmacy and the tolerability of sumatriptan: a large-scale, prospective study.

Polypharmacy (the prescription of more than one therapy for a single patient) and subcutaneous (s.c.) sumatriptan tolerability were prospectively studied in 12,339 migraineurs, each followed for up to 1 year. Inclusion/exclusion criteria were minimal and mirrored United States Imitrex labeling. Drug usage and compliance monitoring were automatically interfaced with prescription refill. Concomitant drugs were used by 79% of patients, with analgesics, antidepressants, and sedatives used most commonly. No adverse interactions between sumatriptan and neurological drugs were found, possibly reflecting relative inability of the former to cross the blood-brain barrier. No difference in cardiovascular adverse events was associated with oral contraceptive use, which was more common than expected. No other drug class influenced adverse event probability, although sample sizes for these comparisons was sometimes <400 patients. This study confirms the prevalence of polypharmacy in migraine, identifies the drugs used, and concludes that, on a population basis, the tolerability of s.c. sumatriptan, when used according to labeled instructions, is unaffected by these concomitant drugs.

Adolescent↗
PubMed1999

Perinatal risk factors for infant hospitalization with viral gastroenteritis.

CONTEXT: A tetravalent vaccine against rotavirus, the most commonly identified etiologic agent of viral gastroenteritis (GE), has recently been licensed for use in the United States. OBJECTIVE: To evaluate whether specific groups of infants might be at sufficiently high risk to warrant a focused rotavirus vaccine policy, we investigated perinatal risk factors for hospitalization with viral GE and rotavirus in the first year of life. DESIGN: Population-based, case-control study. SETTING: Washington State linked birth certificate and hospital discharge abstracts from 1987 through 1995. PATIENTS: Infants, 1 through 11 months of age, hospitalized for viral GE (N = 1606) were patients in this study. Control subjects were 8084 nonhospitalized infants, frequency-matched to patients on year of birth. PRIMARY OUTCOME MEASURE: Maternal and infant characteristics associated with infant hospitalization for viral GE. RESULTS: We found a significant association between birth weight and the risk for hospitalization. Very low birth weight infants (<1500 g) were at the highest risk (odds ratio [OR] 2.6; 95% confidence interval [CI]: 1.6,4.1);, low birth weight infants (1500-2499 g), at intermediate risk (OR 1.6; 95% CI: 1.3,2.1); and large infants (>4000 g), at reduced risk (OR 0.8; 95% CI: 0.6,0.9). Other characteristics associated with GE hospitalization were male gender (OR 1.4; 95% CI: 1.3,1.6); maternal smoking (OR 1.2; 95% CI: 1.1,1. 4); unmarried mother (OR 1.2; 95% CI: 1.1,1.4); Medicaid insurance (OR 1.4; 95% CI: 1.3,1.7); and maternal age <20 years (OR 1.2; 95% CI: 1.0,1.5). Infants born October through December were at decreased risk for hospitalization (OR 0.8; 95% CI: 0.7,0.9), as were infants born to Asian mothers (OR 0.5; 95% CI: 0.3,0.7), and infants born to mothers >34 years of age (OR 0.7; 95% CI: 0.6,0.9). Using these factors, the area under a receiver operating characteristic curve was 0.63. Therefore, to achieve a sensitivity of 90% in identifying high-risk infants, specificity would fall to 10%. Subanalyses of children admitted for viral GE during the peak of the Northwest rotavirus season (January to March) and children with confirmed rotavirus infection demonstrated similar risk factors and receiver operating characteristic curves. CONCLUSION: We conclude that a focused rotavirus vaccination policy using readily identifiable potential high-risk groups would be unlikely to prevent most infant hospitalizations associated with rotavirus infection. However, the safety of rotavirus vaccine in low birth weight and premature infants must be established, because these children appear to be at greater risk for hospitalization with viral GE and rotavirus.

Analysis of Variance↗
PubMed1998

Time-dependence and cell-type specificity of synergistic neurotrophin actions on spiral ganglion neurons.

The neurotrophins brain-derived neurotrophin (BDNF) and neurotrophin-3 (NT-3) synergistically enhance survival of spiral ganglion neurons such that simultaneous exposure to both compounds produces a larger response than would be expected from their individual effects. To elucidate the functional role of this neurotrophin interaction, we examined its temporal and cell-type specificity in vitro for both mouse and gerbil spiral ganglion neurons. Synergistic effects were transient; they were maximal within the first two postnatal days and declined during the first postnatal week. Both neurotrophins were, however, still efficacious at increasing cell survival. After postnatal day 10, the effects of coexposure to BDNF and NT-3 were additive rather than synergistic. Synergism declined more rapidly in mouse than gerbil neurons, reflecting the difference in cochlear development for each species. Only neurons without peripherin epitopes, putative type I neurons, showed synergistic survival effects; survival of peripherin-expressing neurons was purely additive. Therefore, during a restricted time period, identical neurotrophin stimuli are capable of preferentially enhancing survival of one class of neurons that compose approximately 95% of the adult spiral ganglion.

Animals↗
PubMed1998

A novel octopamine receptor with preferential expression in Drosophila mushroom bodies.

Octopamine is a neuromodulator that mediates diverse physiological processes in invertebrates. In some insects, such as honeybees and fruit flies, octopamine has been shown to be a major stimulator of adenylyl cyclase and to function in associative learning. To identify an octopamine receptor mediating this function in Drosophila, putative biogenic amine receptors were cloned by a novel procedure using PCR and single-strand conformation polymorphism. One new receptor, octopamine receptor in mushroom bodies (OAMB), was identified as an octopamine receptor because human and Drosophila cell lines expressing OAMB showed increased cAMP and intracellular Ca2+ levels after octopamine application. Immunohistochemical analysis using an antibody made to the receptor revealed highly enriched expression in the mushroom body neuropil and the ellipsoid body of central complex, brain areas known to be crucial for olfactory learning and motor control, respectively. The preferential expression of OAMB in mushroom bodies and its capacity to produce cAMP accumulation suggest an important role in synaptic modulation underlying behavioral plasticity.

Adrenergic Agents↗
PubMed1998

Influence of bromodeoxyuridine radiosensitization on malignant glioma patient survival: a retrospective comparison of survival data from the Northern California Oncology Group (NCOG) and Radiation Therapy Oncology Group trials (RTOG) for glioblastoma multiforme and anaplastic astrocytoma.

PURPOSE: To examine the effect of treatment using Bromodeoxyuridine (BrdU) during radiation therapy on malignant glioma patient survival by comparing historical survival data from several large clinical trials. METHODS: A retrospective analysis of patient data from Radiation Therapy Oncology Group (RTOG) trials 74-01, 79-18, and 83-02 and the Northern California Oncology Group (NCOG) study 6G-82-1 was conducted. Patient data was supplied by both groups, and analyzed by the RTOG. Pretreatment characteristics including age, extent of surgery, Karnofsky Performance Status (KPS), and histopathology were collected; the only treatment variable evaluated was the use of BrdU during radiation therapy. Radiation dose, dose-fractionation schedule, use of chemotherapy, and/or type of chemotherapy was not controlled for in the analyses. Univariate and multivariate analyses were conducted to examine the potential treatment effect of BrdU on patient survival. RESULTS: Data from 334 patients treated with BrdU on NCOG 6G-82-1 and 1743 patients treated without BrdU on 3 RTOG studies was received. Patients were excluded from the review if confirmation of eligibility could not be obtained, if the patient was ineligible for the study they entered, if central pathology review was not done, or if radiotherapy data was not available. Patients treated according to the RTOG studies had to start radiotherapy within 4 weeks of surgery; no such restriction existed for the NCOG studies. To ensure comparability between the studies, patients from the NCOG studies who began treatment longer than 40 days from surgery were also excluded. The final data set included 296 cases from the NCOG studies (89%) and 1478 cases from the RTOG studies (85%). For patients with glioblastoma multiforme (GBM) the median survival was 9.8 months in the RTOG studies and 13.0 months in the NCOG trial (p < 0.0001). For patients with AA the median survival was 35.1 months for the RTOG studies and 42.8 months in the NCOG trial (p = 0.126). Univariate results showed consistent results favoring BrdU among patients over 30 years of age, across the extent of surgery, and for GBM patients. A proportional hazards regression model that included treatment, histopathology, KPS, age, and extent of surgery demonstrated that treatment with BrdU was included in the best model only for the GBM group of patients (risk ratio 0.83). CONCLUSIONS: Because of the heterogeneity of the treatment groups, including potentially important differences in pathology reviewers assessment of nonglioblastoma cases, differences in radiation dose and schedules, and chemotherapy during or after radiation, these analyses cannot provide the definitive answer as to whether BrdU given during radiation therapy improves survival in patients with malignant glioma. There does appear to be a favorable treatment effect seen in patients with GBM, with a lesser effect in patients with AA.

Adolescent↗
PubMed1998

Integrin-mediated short-term memory in Drosophila.

Volado is a new memory mutant of Drosophila. The locus encodes two isoforms of a new alpha-integrin, a molecule that dynamically mediates cell adhesion and signal transduction. The Volado gene is expressed preferentially in mushroom body cells, which are neurons known to mediate olfactory learning in insects. Volado proteins are concentrated in the mushroom body neuropil, brain areas that contain mushroom body processes in synaptic contact with other neurons. Volado mutants display impaired olfactory memories within 3 min of training, indicating that the integrin is required for short-term memory processes. Conditional expression of a Volado transgene during adulthood rescues the memory impairment. This rescue of memory is reversible, fading over time along with expression of the transgene. Thus the Volado integrin is essential for the physiological processes underlying memory. We propose a model in which integrins act as dynamic regulators of synapse structure or the signalling events underlying short-term memory formation.

Amino Acid Sequence↗