Fred L. Ramsey

Primary CNS lymphoma treated with osmotic blood-brain barrier disruption: prolonged survival and preservation of cognitive function.

Combination chemotherapy with or without radiotherapy has had only modest efficacy in the treatment of primary CNS lymphoma. Median survival of these patients, treated primarily with radiotherapy, is 13 months; 5-year survival is less than 5%. Thirty consecutive non-acquired immune deficiency syndrome patients with primary CNS lymphoma were treated with barrier-dependent chemotherapy using intraarterial mannitol to open the blood-brain barrier (BBB). Follow-up included extensive neuropsychologic testing of all patients. Thirteen patients received cranial radiation 1 to 9 months before referral (group 1). Seventeen patients received initial BBB disruption chemotherapy with subsequent radiation only for tumor progression or recurrence (group 2). The difference in median survivals from diagnosis--17.8 months for group 1 and 44.5 months for group 2--was statistically significant (P = .039). Group 1 survival is comparable with the 20-month median survival of a historical series of patients (n = 208) treated with radiotherapy with or without chemotherapy. Group 2 patient survival represents an advance in the survival of CNS lymphoma and was associated with preservation of cognitive function in six of seven nonirradiated complete responders observed for 1 to 7 years. Patient toxicity was manageable in this intensive therapeutic regimen. In this series, a plateau in survival curves suggests that a major portion of these patients may be cured without the neuropsychologic sequelae associated with cranial radiation.

Experimental separation of effects of consumers on sessile prey in the low zone of a rocky shore in the Bay of Panama: direct and indirect consequences of food web complexity

The effects of predation by a diverse assemblage of consumers on community structure of sessile prey was evaluated in the low rocky intertidal zone at Taboguilla Island in the Bay of Panama. Four functional groups of consumers were defined: (1) large fishes, (2) small fishes and crabs, (3) herbivorous molluscs, and (4) predaceous gastropods, (l) and (2) included fast-moving consumers and (3) and (4) included slow-moving consumers. Experimental treatments were: no consumers deleted (all groups present), most combinations of deletions of single groups (i.e., one group absent, three present), pairs of groups deleted (two absent, two present), trios of groups deleted (three absent, one present), and the entire consumer assemblage deleted (all groups absent). Changes in abundance (percent cover) of crustose algae, solitary sessile invertebrates, foliose algae, and colonial sessile invertebrates were quantified periodically in 2–4 plots of each treatment from February 1977 to January 1980 after the initiation of the experiment in January 1977. Space on this shore is normally dominated by crustose algae; foliose algae, solitary sessile invertebrates, and colonial sessile invertebrates are all rare. After deletion of all consumers, ephemeral green algae increased from 0 to nearly 70% cover. Thereafter, a succession of spatial dominants occurred, with peak abundances as follows: the foliose coralline alga Jania spp. by July 1977, the barnacle Balanus inexpectatus by April 1978, and the rock oyster Chama echinata by January 1980. Although no longer occupying primary rock space, Jania persisted as a dominant or co-dominant turf species (with the brown alga Giffordia mitchelliae and/or the hydrozoan Abietinaria sp.) by colonizing shells of sessile animals as they became abundant instead of the rock surface. Multivariate analysis variance (MANOVA) indicated that the effect of each group was as follows. Molluscan herbivores grazed foliose algae down to the grazer-resistant, but competitively inferior algal crusts, altered the relative abundances of the crusts, and inhibited recruitment of sessile invertebrates. Predaceous gastropods reduced the abundance of solitary sessile animals. Small fishes and crabs, and large fishes reduced the cover of solitary and colonial sessile animals and foliose algae, although they were incapable of grazing the foliose algae down to the rock surface. Many of the effects of each consumer group on prey groups or species were indirect; some effects were positive and some were negative. The variety of these indirect effects was due to both consumer-prey interactions among the consumers, and competitive or commensalistic interactions among the sessile prey. Comparison of the sum of the effects of each of the single consumer groups (i.e., the sum of the effect observed in treatments with one group absent, three present) with the total effects of all consumers (i.e., the effect observed in the treatment with all groups absent) indicates that a “keystone” consumer was not present in this community. Rather, the impacts of the consumer groups were similar but, due to dietary overlap and compensatory changes among the consumers, not readily detected in deletions of single consumer groups. The normally observed dominance of space by crustose algae is thus maintained by persistent, intense predation by a diverse assemblage of consumers on potentially dominant sessile animals and foliose algae. The large difference in structure between this and temperate intertidal communities seems due to differences in degree, not kind of ecological processes which produce the structure.

Covariate Adjustments to Effective Area in Variable-Area Wildlife Surveys

The problem is that of adjusting estimates of effective area surveyed in line transect or variable circular plot wildlife surveys for covariates that are known to influence delectability. We present a model where this can be accomplished within a general linear models framework (Nelder and Wedderburn, 1982, Journal of the Royal Statistical Society, Series A 135, 370-384). The model treats effective area as a scale parameter for detection areas, and uses the logarithm of effective area as a link to the covariates. Maximum likelihood results are presented along with least squares estimates that provide good starting values for iterative searches. We apply the methodology to a situation arising in an avian survey of Saipan Island.

A Bayesian approach to bioassay.

SUMMARY A prior distribution for the class of continuous, non-decreasing potency curves is introduced. The Bayes posterior distribution resulting from an assay experiment with quantal responses is discussed. Several examples are presented where a posterior modal function is used to summarize the posterior distribution. The examples illustrate the value of obtaining smooth estimates of potency and the value of experimental designs using many doses with few observations per dose.

An Adaptive Procedure for Sampling Animal Populations

SUMMARY We consider an adaptive stratified sampling procedure for animal populations in which the sample size in a given stratum or primary unit depends on the observations obtained in previous strata or primary units. This method provides a more efficient way of sampling sparse but highly clustered populations. Two sampling approaches are considered. The first is a design unbiased strategy as the estimate of population density is unbiased through design-induced factors such as the random selection of sites in each stratum. The second is called a model unbiased strategy as the density estimate is unbiased under the model assumed for the spatial distribution of the population. The theory is demonstrated by reference to sampling from a shrimp population.

Dispersed and Undispersed Dependency

Abstract This study was aimed at developing a measure of Kellys concept of dispersion of dependency and providing evidence for its usefulness in differentiating degree of dispersion of dependency. Smith and Grassles (1977) adaptation of Hurlberts diversity index, a measure used by biologists to differentiate degrees of species diversity, was applied to dependency grids, specifically “being helped” grids. The diversity index was shown to be both useful in differentiating prototypes of relatively dispersed and undispersed grids and robust. Furthermore, evidence was provided for its predictive validity using predictions made by Kelly concerning dependency construing associated with differences in dispersion of dependency. Greater dispersion of dependency was related to making more discriminations about dependencies, and undispersed dependency was related to relatively impermeable and preemptive construing. Thus the measure was shown to be satisfactory for identifying dispersion of dependency, such that, u...

Effects of Gd-DTPA after osmotic BBB disruption in a rodent model : toxicity and MR findings

Objective This experiment was done to evaluate the gross neurotoxicity of intravenous Gd-DTPA administered in conjunction with osmotic blood-brain barrier (BBB) disruption and to image a human small cell lung carcinoma intracerebral tumor xenograft before and after osmotic BBB disruption. Materials and Methods Neurotoxicity studies were performed in normal Sprague-Dawley rats following osmotic BBB disruption by the injection of 25% mannitol in the right internal carotid artery and intravenous administration of Gd-DTPA (n = 10). Animals were observed for major neurologic changes such as seizure or substantial motor defects, and after death neuropathologic examination was performed. Human small cell lung carcinoma cells were implanted intracerebrally in athymic nude rats (n = 4). Gadopentetate dimeglumine was injected intravenously and serial T1-weighted images were obtained. Blood-brain barrier disruption was produced in each animal, followed by a second dose of intravenous Gd-DTPA, and imaging studies were repeated. Results No gross neurologic toxicity was observed. Tumors showed dense enhancement in a small area, and BBB disruption resulted in marked enhancement in most of the gray matter of the right cerebral hemisphere. Conclusion Gadopentetate dimeglumine appears to be safe in doses up to 21 mmol/m2 in conjunction with barrier disruption in rats. A human small cell lung carcinoma intracerebral xenograft provides a useful method to study brain tumors.

A closer look at detectability

The theory underlying line transect and variable circular plot surveys—distance sampling—begins with an assumed detectability function, giving the probabilities of detecting animals at different distances from the observers path. The nature of these probabilities is unspecified in the general development, leaving users to question whether the actual probability structure matters. In particular, may one use the methodology in surveys where animals at the same distance have different probabilities of detection? This paper presents three examples where probabilities come from different assumptions: from the random placement of transects; from the uniform distribution of animals over the study region; and from cues randomly detected by the observer. These exemplify situations where detectability may not be a function of distance alone. Horvitz-Thompson estimators are displayed which can be used in each example, but some estimators require measuring features other than distance. A result concerning optimally weighted Horvitz-Thompson estimators shows that all three can be brought under the same umbrella if detection areas are measured instead of detection distances and if animals are uniformly distributed.

Dexamethasone decreases the delivery of tumor-specific monoclonal antibody to both intracerebral and subcutaneous tumor xenografts

The effect of dexamethasone on the delivery of monoclonal antibody L6 IgG to intracerebral and subcutaneous LX-1 small cell lung carcinoma xenografts was evaluated in nude rats (n = 157). Dexamethasone (0, 8, or 24 mg/m2) was given 18 hours before infusion of L6 IgG, with or without osmotic disruption of the blood-brain barrier. Compared with controls, the 8 mg/m2 dose decreased delivery of L6 IgG (12-37%) to all tissues, but the only significant decrease (P < 0.001) was in the subcutaneous tumor (37%). In the 24 mg/m2 group, L6 IgG delivery was significantly (P < 0.001) decreased to all tissues (37-60%). Dexamethasone had no effect on plasma levels. Barrier disruption significantly (P < 0.0001) increased L6 IgG delivery to intracranial tumor and surrounding brain, but not to subcutaneous tumor or plasma. The percentage of decremental effect of dexamethasone on L6 IgG delivery was the same with and without barrier disruption and was not associated with the time the animals were killed (P > 0.05). Compared with controls, the ratio of intracranial tumor to normal brain showed no change with dexamethasone, but the ratios of both intracranial and subcutaneous tumors to plasma significantly (P < 0.002) decreased with both doses. The in vitro cell binding capacity of L6 IgG to LX-1 cells remained unchanged after incubation of cells with dexamethasone over a 3-log concentration for 4 days, demonstrating no effect on antigen expression. This study suggests that dexamethasone has a clinically relevant generalized (i.e., central nervous system and systemic) vascular effect on permeability to L6 IgG monoclonal antibody.

Small Sample Power Functions for Nonparametric Tests of Location in the Double Exponential Family

Abstract Eight nonparametric tests of location are examined in a small sample setting. Power functions are presented for samples drawn from the double exponential distribution. The results provide an example where the asymptotically most powerful rank test (the Mood median test) performs poorly for alternatives which are not very close to the null hypothesis.