Ethics in phase II trials of cancer therapies.
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Clinical Protocols↗
Biomedical subjects
M Davis
Publications and source records attributed to M Davis.
A First Comparison of the Surface Brightness Fluctuation Survey Distances with the Galaxy Density Field: Implications for H0 and Omega.
We compare the peculiar velocities measured in the surface brightness fluctuation survey of galaxy distances with the predictions from the density fields of the IRAS 1.2 Jy flux-limited redshift survey and the optical redshift survey (ORS) to derive simultaneous constraints on the Hubble constant H0 and the density parameter beta=Omega0.6&solm0;b, where b is the linear bias. We find that betaI=0.42+0.10-0.06 and betaO=0.26+/-0.08 for the IRAS and ORS comparisons, respectively, and that H0=74+/-4 km s-1 Mpc (with an additional 9% uncertainty due to the Cepheids themselves). The match between predicted and observed peculiar velocities is good for these values of H0 and beta, and although there is covariance between the two parameters, our results clearly point toward low-density cosmologies. Thus, the unresolved discrepancy between the "velocity-velocity" and "density-density" measurements of beta continues.
Journal Article↗
The Discovery of a High-Redshift Quasar without Emission Lines from Sloan Digital Sky Survey Commissioning Data.
We report observations of a luminous unresolved object at redshift z=4.62, with a featureless optical spectrum redward of the Lyalpha forest region, discovered from Sloan Digital Sky Survey commissioning data. The redshift is determined by the onset of the Lyalpha forest at lambda approximately 6800 Å and a Lyman limit system at lambda=5120 Å. A strong Lyalpha absorption system with weak metal absorption lines at z=4.58 is also identified in the spectrum. The object has a continuum absolute magnitude of -26.6 at 1450 Å in the rest frame (h0=0.5, q0=0.5) and therefore cannot be an ordinary galaxy. It shows no radio emission (the 3 sigma upper limit of its flux at 6 cm is 60 µJy), indicating a radio-to-optical flux ratio at least as small as that of the radio-weakest BL Lacertae objects known. It is also not linearly polarized to a 3 sigma upper limit of 4% in the observed I band. Therefore, it is either the most distant BL Lac object known to date, with very weak radio emission, or a new type of unbeamed quasar, whose broad emission line region is very weak or absent.
Journal Article↗
A distance to the galaxy NGC4258 from observations of Cepheid variable stars.
Cepheid variable stars pulsate in a way that is correlated with their intrinsic luminosity, making them useful as 'standard candles' for determining distances to galaxies; the potential systematic uncertainties in the resulting distances have been estimated to be only 8-10%. They have played a crucial role in establishing the extragalactic distance scale and hence the value of the Hubble constant. Here we report observations of Cepheids in the nearby galaxy NGC4258; the distance calculated from the Cepheids is 8.1 +/- 0.4 Mpc, where the uncertainty does not include possible systematic errors. There is an independently determined geometric distance to this galaxy of 7.2 +/- 0.5 Mpc, based on the observed proper motions of water masers orbiting the central black hole; the distances differ by 1.3sigma. If the maser-based distance is adopted and the Cepheid distance scale revised accordingly, the derived value of the Hubble constant would increase by 12 +/- 9%, while the expansion age of the Universe would decrease by the same amount.
Journal Article↗
The extended amygdala: are the central nucleus of the amygdala and the bed nucleus of the stria terminalis differentially involved in fear versus anxiety?
Although there is a close correspondence between fear and anxiety, and the study of fear in animals has been extremely valuable for understanding the neural basis of anxiety, it is also clear that a richer animal model of human anxiety disorders would include measures of both stimulus-specific fear and something less stimulus specific, more akin to anxiety. Patients with posttraumatic stress syndrome seem to show normal fear reactions but abnormal anxiety measured with the acoustic startle reflex. Studies in rats, also using the startle reflex, indicate that highly processed explicit cue information (lights, tones) activates the central nucleus of the amygdala, which projects to and modulates the acoustic startle pathway in the brain stem. Less explicit information, such as that produced by exposure to a threatening environment or by intraventricular administration of corticotropin-releasing hormone, may activate another part of the extended amygdala, the bed nucleus of the stria terminalis, which also projects to the startle pathway. Because this information may be less specific and of long duration, activation of the bed nucleus of the stria terminalis may mediate anxiety, whereas activation of the central nucleus of the amygdala may mediate stimulus-specific fear.
Amygdala↗
Cortical afferents to the extended amygdala.
The projections of the cerebral cortex to the extended amygdala were studied in the rat using anterograde and retrograde tract-tracing techniques. Most cortical areas with strong projections to the extended amygdala preferentially targeted either the medial extended amygdala (including the medial amygdalar nucleus, ventromedial substantia innominata, and the medial part of the bed nucleus the stria terminalis) or the central extended amygdala (including the central amygdalar nucleus, dorsolateral substantia innominata, and the lateral part of the bed nucleus of the stria terminalis). Some cortical areas, however, had equal projections to both medial and central portions. The main areas projecting preferentially to the medial extended amygdala were the ventral subiculum, infralimbic cortex, ventral agranular insular area, and the rostral part of the ventrolateral entorhinal area. The main areas projecting preferentially to the central extended amygdala were the prefrontal cortex, viscerosensory and somatosensory portions of the insular cortex, and the amygdalopiriform transitional area. It is suggested that these cortical inputs may be important for cognitive, mnemonic, and affective aspects of emotional and motivated behavior.
Afferent Pathways↗
The Women's Health Trial Feasibility Study in Minority Populations: changes in dietary intakes.
This randomized clinical trial examined the feasibility of low-fat dietary interventions among postmenopausal women of diverse backgrounds. During 1992-1994, 2,208 women aged 50-79 years, 28% of whom were black and 16% Hispanic, enrolled at clinics in Atlanta, Georgia, Birmingham, Alabama, and Miami, Florida. Intervention/support groups met periodically with a nutritionist to reduce fat intake to 20% of energy and to make other diet modifications. At 6 months postrandomization, the intervention group reduced fat intake from 39.7% of energy at baseline to 26.4%, a reduction of 13.3% of energy, compared with 2.3% among controls. Saturated fatty acid and cholesterol intakes were reduced, but intakes of fruits and vegetables, but not grain products, increased. Similar effects were observed at 12 and 18 months. Black and non-Hispanic white women had similar levels of reduction in fat, but the decrease in Hispanic women was less. Changes did not vary significantly by education. While bias in self-reported intakes may have resulted in somewhat overestimated changes in fat intake, the reported reduction was similar to the approximately 10% of energy decrease found in most trials and suggests that large changes in fat consumption can be attained in diverse study populations and in many subgroups.
Aged↗
Radiation target analysis indicates that phenylalanine hydroxylase in rat liver extracts is a functional monomer.
The minimal enzymatically functional form of purified rat hepatic phenylalanine hydroxylase (PAH) is a dimer of identical subunits. Radiation target analysis of PAH revealed that the minimal enzymatically active form in crude extracts corresponds to the monomer. The 'negative regulation' properties of the tetrahydrobiopterin cofactor in both crude and pure samples implicates a large multimeric structure, minimally a tetramer of PAH subunits. Preincubation of the samples with phenylalanine prior to irradiation abolished this inhibition component without affecting the minimal functional unit target sizes of the enzyme in both preparations. The characteristics of rat hepatic PAH determined by studies of the purified enzyme in vitro may not completely represent the properties of PAH in vivo.
Animals↗
Extraskeletal Ewing's sarcoma.
BACKGROUND: Ewing's sarcoma usually is identified as a primary malignancy of bone affecting children and young adults. Extraskeletal Ewing's sarcoma is rare, and very few data are available addressing optimal surgical and oncologic treatment modalities. METHODS: The authors chose to review retrospectively 24 patients with extraskeletal Ewing's sarcoma treated at the study institution with modern multimodality therapies. Anatomic location, tumor size, patient age at diagnosis, stage of disease at the time of diagnosis, surgical margins, radiation dose, and the type and dose of chemotherapy were documented for every patient. Follow-up averaged 64 months for surviving patients. RESULTS: The overall 5-year survival rate was 61% and the disease free survival rate was 54%. A multivariate analysis found that younger age at the time of diagnosis was associated with improved 5-year survival and disease free survival (P = 0.008 and P = 0.005, respectively). Patients who underwent wide resection and less-than-wide resection had better overall survival (P = 0.001 and P = 0.015, respectively) and disease free survival (P = 0.002 and P = 0.024) compared with those who underwent no attempt at surgical resection. Patients who underwent a wide resection had an improved overall survival compared with those who underwent a less-than-wide resection (P = 0.045). The size of the lesion (P = 0.277) and the presence of metastatic disease at the time of diagnosis (P = 0.219) were not found to be significant prognostic factors. CONCLUSIONS: Age and surgical treatment were found to be important prognostic variables in the treatment of extraskeletal Ewing's sarcoma. No other variables, such as tumor size, tumor location, stage of disease, or radiation therapy, were found to improve survival. Surgical resection should be considered for all patients with extraskeletal Ewing's sarcoma.
Adolescent↗
Pain pathways involved in fear conditioning measured with fear-potentiated startle: lesion studies.
It is well established that the basolateral amygdala is critically involved in the association between an unconditioned stimulus (US), such as a foot shock, and a conditioned stimulus (CS), such as a light, during classic fear conditioning. However, little is known about how the US (pain) inputs are relayed to the basolateral amygdala. The present studies were designed to define potential US pathways to the amygdala using lesion methods. Electrolytic lesions before or after training were placed in caudal granular/dysgranular insular cortex (IC) alone or in conjunction with the posterior intralaminar nuclei of the thalamus (PoT/PIL), and the effects on fear conditioning were examined. Pretraining lesions of both IC and PoT/PIL, but not lesions of IC alone, blocked the acquisition of fear-potentiated startle. However, post-training combined lesions of IC and PoT/PIL did not prevent expression of conditioned fear. Given that previous studies have shown that lesions of PoT/PIL alone had no effect on acquisition of conditioned fear, these results suggest that two parallel cortical (insula-amygdala) and subcortical (PoT/PIL-amygdala) pathways are involved in relaying shock information to the basolateral amygdala during fear conditioning.
Animals↗
Inhibition of thymocyte positive selection by natural MHC: peptide ligands.
The 3A9 transgenic mouse line carries the rearranged TCR genes from a T cell hybridoma that recognizes hen egg lysozyme peptide 46-61 in the context of MHC class II Ak molecules. As expected, positive selection of immature 3A9 thymocytes to become mature CD4+ 8- T cells was efficient on the "selecting" CBA (H-2k) genetic background but not on the "non-selecting" C57BL/6 (H-2b) background. Surprisingly, positive selection was also inefficient on the CBA x C57BL/6 F1 background (H-2kb). We present evidence that expression of A(beta)b molecules on thymus epithelium (in conjunction with A(alpha)b or A(alpha)k molecules) inhibits the positive selection of 3A9 thymocytes mediated by A(alpha)k:A(beta)k complexes, in a process evocative of peptide antagonism of mature T cells.
Animals↗
Development of novel benzimidazole riboside compounds for treatment of cytomegalovirus disease.
Benzimidazole ribosides are a new class of compounds with novel mechanisms of action against CMV. One compound in this series, BDCRB, inhibits CMV DNA processing by the UL89 gene product (putative terminase), but rapid metabolism to an inactive compound makes it unsuitable for development as a medicine. Another benzimidazole analogue, 1263W94, has many characteristics that make it an attractive candidate for development, including high potency in vitro, selectivity, good oral bioavailability, and lower toxicity than therapies currently available for treatment of CMV disease. Initial clinical trials have provided encouraging results, including good tolerability and linear pharmacokinetics over a wide dose range. Ongoing and planned clinical trials that will study the safety and tolerability of repeated dosing and evaluate the in vivo antiviral activity and ocular penetration of 1263W94, will help to determine the potential of this drug as an improved therapy for CMV disease.
Antiviral Agents↗
Enhancement of the acoustic startle response in rats by the dopamine D1 receptor agonist SKF 82958.
RATIONALE: The present series of experiments was conducted in order to assess the nature of dopaminergic modulation of the acoustic startle response using agonists and antagonists specific for dopamine D1 and D2 receptors. OBJECTIVES: The objective of the present study was to demonstrate an enhancement of the acoustic startle response by dopamine D1 receptor agonists and to characterize this effect pharmacologically in terms of dose-response and selective antagonism at both the dopamine D1 and D2 receptor using a varied range of startle-eliciting intensities. METHODS: Male Sprague-Dawley rats were injected subcutaneously with the dopamine D1 receptor agonist SKF 82958 (0, 0.01, 0.1, 1, or 3 mg/kg) or SKF 81297 (3 mg/kg) and their startle response was measured across a range of startle-eliciting intensities. For testing with the dopamine D1 or D2 receptor antagonists, animals received injections of either SCH 23390 (0.01 and 0.1 mg/kg) or raclopride (0.1 and 1 mg/kg) 10 min before the challenge with SKF 82958 (1 mg/kg). RESULTS: Systemic administration of SKF 82958 produced a marked enhancement of startle over a wide range of startle intensities. This effect was dose-dependent, with a dose of 1 mg/kg producing the maximal amount of startle enhancement at each intensity. SKF 81297 (3 mg/kg) also produced a robust enhancement of startle. Pretreatment with SCH 23390 produced a dose-dependent blockade of the enhancement of startle by SKF 82958. Pretreatment with raclopride blocked the enhancement of startle by SKF 82958 at the low intensities and attenuated the enhancement at the high intensities. CONCLUSIONS: These data suggest that dopamine D1 receptor agonists enhance the acoustic startle response. Furthermore, this effect is dependent on a cooperative type of D1/D2 receptor interaction whereby D2 receptor activation is necessary for the full expression of the D1 receptor-mediated enhancement of startle.
Animals↗
Evaluation of small intestine submucosa and acellular dermis as diaphragmatic prostheses.
BACKGROUND/PURPOSE: The repair of large congenital diaphragmatic defects in the neonate continues to be a challenge. Polytetrafluoroethylene (PTFE) is the synthetic material most widely used for reconstruction in instances of partial and complete diaphragmatic agenesis. Recurrent hernia is a frequent complication, because this material does not grow with the infant. This study evaluates two novel materials; small intestine submucosa (SIS; Cook Biotech, Lafayette, IN), and acellular dermis (AlloDerm; Lifecell Corp, The Woodland, TX) for diaphragm reconstruction in growing animals. METHODS: Sprague-Dawley rats (100 g, n = 87) were anesthetized and underwent laparotomy. The control group (n = 18) underwent a sham laparotomy with a left subcostal incision and closure. The other two groups underwent central excision of the left hemidiaphragm (50% loss) and reconstruction with either a SIS (n = 35) or AlloDerm (n = 19) patch sutured circumferentially with 6-0 prolene. Seventy-two animals survived the operation, and were killed at five separate time intervals (2 weeks, 1, 2, 3, and 4 months). Chest radiographs were performed monthly and before death. Radiographs were reviewed in a blinded fashion by two observers as were the necropsies, and rib deformity was noted if present. Histological examination of the diaphragm patch was performed in each animal. RESULTS: There was no evidence of rib deformity noted on gross examination at necropsy or on chest radiograph in either experimental group. At necropsy, all patches were intact without hernia, eventration, or contraction. Histology findings initially showed acute and chronic inflammatory changes in both patch materials that lessened at the 2-month time interval. Both prosthetic patches began to thin at 3 months and was most prominent in the SIS rats. At 4 months, both SIS and AlloDerm remained viable without evidence of necrosis. Each patch showed evidence of fibroblastic incorporation and small capillary ingrowth. These changes were more prominent in the AlloDerm group. There was no evidence of skeletal muscle ingrowth. CONCLUSIONS: These data indicate SIS and AlloDerm may be useful materials for prosthetic repair in instances of partial or total agenesis of the diaphragm. Further investigation in a large animal model over a longer duration is indicated.
Animals↗
Absence of EWS/FLI1 fusion in olfactory neuroblastomas indicates these tumors do not belong to the Ewing's sarcoma family.
The balanced reciprocal translocation t(11;22)(q24;q12) is a specific molecular marker for the Ewing's sarcoma family of tumors (ESFT). Based on the detection of this translocation in some olfactory neuroblastomas (ONBs), it has been proposed that ONBs also belong to the ESFT. Others have challenged this hypothesis; however, the rarity of ONBs, as well as the lack of molecular techniques that work reliably on formalin fixed tissue, have precluded the molecular analysis of a significant number of cases. We evaluated the immunophenotypic and molecular features of 17 paranasal small round neuroectodermal tumors using routinely fixed tissue. Probes localizing to 22q12 (EWS) and 11q24 (FLI-1) were used in a standard 2-color fluorescence in situ hybridization (FISH) assay to evaluate EWS/FLI1 fusion on the der(22). Sixteen tumors were mic-2 negative, whereas 1 tumor was mic-2 positive, compatible with ONB and ESFT, respectively. Thirteen of 15 ONBs could be evaluated by FISH, and all 13 were negative for the EWS/FLI1 fusion. Distinct fusion signals were identified in the single paranasal ESFT. Our findings indicate that ONBs lack the EWS/FLI1 fusion and are unrelated to the ESFT; however, true ESFTs may rarely occur as primary sinonasal tumors.
Adolescent↗
Systemic and pulmonary oxidative stress in idiopathic pulmonary fibrosis.
An oxidant/antioxidant imbalance has been proposed in patients with idiopathic pulmonary fibrosis (IPF). We tested this hypothesis by measuring various parameters of the oxidant/antioxidant balance in the plasma of 12 patients with IPF (7 nonsmokers and 5 smokers); in the bronchoalveolar lavage fluid (BALF) of 24 patients with IPF (17 nonsmokers and 7 smokers) and 31 healthy subjects (23 nonsmokers and 8 smokers). The trolox equivalent antioxidant capacity (TEAC) in plasma and BALF was lower in nonsmoking patients with IPF (plasma 0.55+/-0.1 mM, p<.001; BALF 4.8+/-1.2 microM, mean +/-SEM, p<.01), compared with healthy nonsmokers (plasma 1.33+/-0.03 mM; BALF 10+/-2 microM). Similar trends in plasma and BALF TEAC were observed in smoking patients with IPF in comparison with healthy smokers. The decrease in BALF TEAC was concomitant with a decrease in BALF protein thiol levels, but the decrease TEAC levels in plasma in IPF patients was not accompanied by a decrease in protein thiol levels. Reduced glutathione (GSH) was lower in BALF in nonsmoking patients with IPF (1.0+/-0.1 microM) compared with healthy nonsmokers (2.3+/-0.2 microM, p<.001). In contrast, GSH levels were higher in smoking patients with IPF (5.2+/-1.1 microM, p<.001) than in nonsmoking patients. GSSG levels were not different in any of the groups. The levels of products of lipid peroxidation measured as thiobarbituric acid reactive substances (TBARS) in plasma and BALF were significantly increased in both smoking (plasma 2.2+/-0.5 microM, p<.01; BALF 0.18+/-0.04 microM, p<.001), and nonsmoking (plasma 2.1+/-0.3 microM, p<.01; BALF 0.22+/-0.05 microM, p<.001) IPF patients, compared with healthy nonsmokers (plasma 1.4+/-0.3 microM; BALF 0.05+/-0.004 microM). These data show evidence of oxidant/antioxidant imbalance in the lungs of patients with IPF, which is also reflected as systemic oxidant stress.
Bronchoalveolar Lavage Fluid↗
Muscimol in the deep layers of the superior colliculus/mesencephalic reticular formation blocks expression but not acquisition of fear-potentiated startle in rats.
Deposits of the retrograde tracer Fluoro-Gold into the ventrolateral nucleus reticularis pontis caudalis labeled neurons in the deep layers of the superior colliculus/mesencephalic reticular formation (deep SC/Me). To test the involvement of this area in the fear-potentiated startle effect, rats were implanted with cannulas into the deep SC/Me and trained for fear-potentiated startle after infusion of the GABA(A) agonist muscimol (0.1 microg/0.5 microl). Two days later, they were tested for fear-potentiated startle. Rats then received a 2nd training session without any infusions, and 2 days later they were reinfused with muscimol (0.1 microg/0.5 microl) and tested for fear-potentiated startle. Local infusion of muscimol into the deep SC/Me completely blocked the expression but not the acquisition of fear-potentiated startle. These results indicate that a synapse in the midbrain is critical for the expression of fear-potentiated startle.
Animals↗
A radiation hybrid map of the rat genome containing 5,255 markers.
A whole-genome radiation hybrid (RH) panel was used to construct a high-resolution map of the rat genome based on microsatellite and gene markers. These include 3,019 new microsatellite markers described here for the first time and 1,714 microsatellite markers with known genetic locations, allowing comparison and integration of maps from different sources. A robust RH framework map containing 1,030 positions ordered with odds of at least 1,000:1 has been defined as a tool for mapping these markers, and for future RH mapping in the rat. More than 500 genes which have been mapped in mouse and/or human were localized with respect to the rat RH framework, allowing the construction of detailed rat-mouse and rat-human comparative maps and illustrating the power of the RH approach for comparative mapping.
Animals↗