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Biomedical subjects

D M Green

Publications and source records attributed to D M Green.

At least 91 records · Page 5Linked to original sources
PubMed1996

Germline WT1 mutations in Wilms' tumor patients: preliminary results.

We conducted a comparative study of the prevalence of germline WT1 mutations in patients with Wilms' tumor. Patients in Group 1 have familial Wilms' tumor, bilateral disease, associated urogenital anomalies, and/or second cancers. Those in Group 2 are unilateral, sporadic Wilms' patients without other associated conditions. Patients with aniridia or Denys-Drash syndrome are known to have WT1 alterations, and are excluded from this study. Preliminary results on 96 subjects show that the overall germline WT1 mutation frequency is low (< 5%). The work to date establishes the feasibility of identifying patients with germline WT1 mutations and, in the future, offering genetic predisposition testing to at-risk relatives. However, genetic predisposition testing of children for WT1 mutations raises many ethical, legal, and psychosocial issues; research is needed to evaluate risks and benefits.

Base Sequence↗
PubMed1996

Focal effects of mononuclear leukocyte transendothelial migration: TNF-alpha production by migrating monocytes promotes subsequent migration of lymphocytes.

In many inflammatory diseases, mononuclear leukocytes (MNLs) accumulate as focal infiltrates in perivascular spaces. We postulated that MNLs migrating through endothelium modify the microenvironment to promote the subsequent migration of additional MNLs into the same area. We found that as monocytes adhere to and migrate spontaneously through an endothelial monolayer, they secrete tumor necrosis factor-alpha (TNF-alpha) and interleukin-1. These cytokines stimulate endothelial cell expression of CD54 (intercellular adhesion molecule-1) and CD106 (vascular cell adhesion molecule-1). Consequently, when freshly isolated MNLs are added to that endothelial monolayer four or more hours later, significantly greater numbers of lymphocytes bind to and migrate through these endothelial monolayers. In addition to its ability to activate endothelial cell adhesion molecules, TNF-alpha induced directed migration of lymphocytes through collagen pads. These results illustrate a potential amplification mechanism by which MNLs moving through a vessel wall may secrete TNF-alpha, leading to the recruitment of additional leukocytes into the same perivascular locus.

Cell Communication↗
PubMed1996

The relative effect of Azone and Transcutol on permeant diffusivity and solubility in human stratum corneum.

PURPOSE: The purpose of this work was to analyse the mechanism of the enhancement of percutaneous penetration demonstrated by the known enhancers Azone and Transcutol. METHODS: Enhancer induced changes in the diffusivity and solubility of a model permeant (4-cyanophenol) in human stratum corneum were monitored (in-vitro) using Attenuated total reflectance Fourier transform infra-red (ATR-FTIR) spectroscopy and compared to the gross effects of the enhancers on flux as measured using simple Franz-type diffusion cells. RESULTS: It has been shown by both the well-established Franz diffusion cell technique and the use of ATR-FTIR spectroscopy that the enhancers studied both increase the flux of cyanophenol across human skin in-vitro by a factor of approximately two. Furthermore, it has been demonstrated by ATR-FTIR that these enhancers are likely to exert their effects by different mechanisms. It is probable that Azone reduces the diffusional resistance of the stratum corneum and that Transcutol increases the solubility of the penetrant in this barrier. CONCLUSIONS: There is increasing interest in the apparently synergistic nature in which certain enhancers appear to work. The exact nature of these multiplicative and/or additive effects is not known although there are numerous suggestions in the current literature. The application of ATR-FTIR spectroscopy to such enhancing systems will allow the mechanisms of the observed enhancements to be probed in greater depth.

Analysis of Variance↗
PubMed1996

Sex and the spread of retrotransposon Ty3 in experimental populations of Saccharomyces cerevisiae.

Mobile genetic elements may be molecular parasites that reduce the fitness of individuals that bear them by causing predominantly deleterious mutations, but increase in frequency when rare because transposition increases their rates of transmission to the progeny of crosses between infected and uninfected individuals. If this is true, then the initial spread of a mobile element requires sex. We tested this prediction using the yeast retrotransposon Ty3 and a strain of Saccharomyces cerevisiae lacking Ty3. We infected replicate isogenic sexual and asexual populations with a galactose-inducible Ty3 element at an initial frequency of 1%. In two of six asexual populations, active Ty3 elements increased in frequency to 38 and 86%, due to the spread in each population of a competitively superior mutant carrying a new Ty3 insertion. Ty3 frequencies increased above 80% in all sexual populations in which transposition was induced in haplophase or in diplophase. Ty3 did not increase in frequency when active during both haplophase and diplophase, apparently because of selective sweeps during adaptation to galactose. Repressed Ty3 elements spread in sexual populations, by increasing sexual fitness. These results indicate that active Ty3 elements are more likely to become established in sexual populations than in asexual populations.

Crosses, Genetic↗
PubMed1996

Focal versus diffuse anaplasia in Wilms tumor--new definitions with prognostic significance: a report from the National Wilms Tumor Study Group.

Anaplasia, defined by the presence of extreme nuclear and mitotic atypia, is a potent marker of adverse prognosis in Wilms tumor (WT). Anaplastic WT cells apparently have increased resistance to therapy rather than increased aggressiveness. The distribution of anaplasia should therefore have critical prognostic relevance. The original definitions for focal anaplasia (FA) and diffuse anaplasia (DA) were based on quantitative rather than topographical criteria and lacked prognostic significance. A new definition was developed based on the distribution of anaplastic changes within the tumor: FA applies only to tumors with anaplasia confined to one or a few discrete loci within the primary tumor, with no anaplasia or marked nuclear atypia elsewhere. This revised definition was evaluated in 165 cases with anaplastic WT entered on the third and fourth National Wilms Tumor Study. Only three relapses and one death occurred among 39 cases with FA, regardless of tumor stage, a result comparable to that for nonanaplastic WT. Eight children with metastases at diagnosis and FA in the primary tumor were alive and free of relapse; 22 of 23 children with stage IV DA WT died of tumor. This new definition reinforces the importance of carefully documenting the exact site from which each tumor section is obtained.

Anaplasia↗
PubMed1996

Decision rules of listeners in spectral-shape discrimination with or without signal-frequency uncertainty.

A correlation technique was used to assess the decision rules of three listeners in two cases of spectral-shape discrimination tasks. In one case the signal frequency was fixed, and in the other it was randomly varied within each block of trials. In order to estimate the decision rule of the listeners, the experimenter superimposed random level perturbations on each frequency component upon each stimulus presentation. Over many trials, correlation coefficients were computed between the random perturbations and the binary responses of the listeners, and were expressed as a function of signal level. For both the fixed- and random-signal cases, the measured correlation functions were in reasonably good agreement with those predicted based on the likelihood-ratio decision rules. Thus the listeners appeared to use information nearly optimally in discriminating spectral shapes. This investigation demonstrated that the correlation technique can be used to reveal the decision rules for cases where the decision statistics are nonlinear functions of the observations.

Auditory Perception↗
PubMed1996

Adaptive psychophysical procedures and imbalance in the psychometric function.

One class of adaptive psychophysical procedures was studied, using simulated and human observers. These procedures are those which require an increase in stimulus intensity after an incorrect response, and a decrease after k successive correct responses. This paper analyzes how step size and the value of k affect the mean and standard deviation of threshold estimates based on a k-down 1-up adaptive procedure. Computer simulations are used to study the bias in threshold estimates, which are most evident when larger step size and small values of k are used. The adaptive procedure can be characterized by a function called the imbalance of the track, the relative probability of adjusting the stimulus either up or down at equal stimulus distances from the equilibrium point. These imbalance functions can be used to understand the threshold biases obtained in the computer simulations. The computer simulations also show that the average number of reversals obtained per trial is dependent on different values of k, but are largely independent of step size. The standard error of the threshold estimates, however, varies systematically with step size, but are nearly independent of k. Finally, we compare the stability of threshold estimates for human listeners using two very different sets of parameters: a very large step size (approximately half the range of the psychometric function) with k = 4, and the conventional k = 3 with an initial 4-dB and a final 2-dB step size.

Acoustic Stimulation↗
PubMed1996

Phase independence of pitch produced by narrow-band sounds.

Three listeners matched the pitch of a simple tone to that of narrow-band complex signals having different phases. The pitch matches were independent of the phases; the frequency of the simple tone approximately equaled the center of gravity of the power spectrum of each complex signal. This result is inconsistent with a model that calculates the pitch of a waveform as the average of instantaneous frequency weighted by the envelope of the waveform.

Humans↗
PubMed1996

The optimum decision rules in the same-different paradigm.

In this paper we derive the optimum (likelihood-ratio) decision statistic for a same-different paradigm. The likelihood ratio is dependent on the degree of correlation between the two observations on each trial. For the two extreme cases in which the observations are either independent or highly correlated, the optimum decision rule is identical to each of two previously suggested decision rules. For these two cases, the receiver-operating characteristic (ROC) curves are calculated. Finally, an experimental procedure is suggested for assessing the decision rule actually used by the observer in a same-different task.

Decision Making↗
PubMed1996

The optimum decision rules for the oddity task.

This paper presents the optimum decision rule for an m-interval oddity task in which m-1 intervals contain the same signal and one is different or odd. The optimum decision rule depends on the degree of correlation among observations. The present approach unifies the different strategies that occur with "roved" or "fixed" experiments (Macmillan & Creelman, 1991, p. 147). It is shown that the commonly used decision rule for an m-interval oddity task corresponds to the special case of highly correlated observations. However, as is also true for the same-different paradigm, there exists a different optimum decision rule when the observations are independent. The relation between the probability of a correct response and d' is derived for the three-interval oddity task. Tables are presented of this relation for the three-, four-, and five-interval oddity task. Finally, an experimental method is proposed that allows one to determine the decision rule used by the observer in an oddity experiment.

Decision Making↗
PubMed1996

Evaluation of a maximum likelihood procedure for measuring pure-tone thresholds under computer control.

An adaptive, maximum likelihood (ML) procedure was assessed as an automated tool for estimating audiometric pure-tone thresholds in the clinic under computer control. Pure-tone air-conduction thresholds were measured from 101 workmen who received annual hearing rechecks as part of their employee hearing conservation program. A pure-tone threshold was measured bilaterally for each of the standard audiometric frequencies in a 15-trial block to yield 60 percent correct detection with the ML procedure. The workmen were tested on a modified "yes-no" task. On a trial, the signal was presented in a visually cued 200-msec observation interval. Each workman then had 1000 msec to make a "yes" response. If the workman did not respond during the 1000-msec response period, then the computer assumed a "no" response. After either the "yes" or "no" response, the computer adjusted the signal level for the next trial. The thresholds measured by ML procedure compared favorably with thresholds measured from the same listeners by conventional (CONV) audiometry. The efficiency of the ML procedure was also compared in terms of the time necessary for an experienced audiologist to instruct the listener and perform CONV audiometry. CONV audiometry (3-4 minutes per listener) required about half of the time needed for the ML procedure (6-7 minutes per listener). The relatively longer time associated with measuring an audiogram with the ML procedure was due primarily to more trials being used to estimate threshold.

Adult↗
PubMed1995

Chemopreventive activity of tamoxifen, N-(4-hydroxyphenyl)retinamide, and the vitamin D analogue Ro24-5531 for androgen-promoted carcinomas of the rat seminal vesicle and prostate.

We evaluated the ability of dietary N-(4-hydroxyphenyl)retinamide; 1 alpha,25-dihydroxy-16-ene-23-yne-26,27-hexafluorocholecalcifero l (Ro24-5531); and tamoxifen to inhibit the development of androgen-promoted carcinomas of the accessory sex organs of male Lobund-Wistar rats. Invasive carcinomas of the seminal vesicle (SV) and anterior prostate (AP) were induced in Lobund-Wistar rats with three different combinations of initiator [N-nitroso-N-methylurea (NMU)] and promoter [testosterone propionate (TP)]: (a) high-dose NMU (30 mg/kg) + high-dose TP (20 mg via implant every 2 months); (b) high-dose NMU + low-dose TP (10 mg implanted every 2 months); or (c) low-dose NMU (15 mg/kg) + low-dose TP. During the period of TP administration, rats were fed a diet supplemented with either N-(4-hydroxyphenyl)retinamide (1 or 2 mmol/kg diet), Ro24-5531 (1.25 or 2.5 nmol/kg diet), tamoxifen (0.5 or 5 mg/kg diet), or vehicle alone. After sacrifice at 8.5 or 11 months, the prostate-seminal vesicle complex from each rat was processed in toto and histologically staged as to the extent of tumor involvement. In animals given low-dose TP, all three agents were significantly effective at reducing the incidence of invasive carcinomas of the SV and, to a lesser degree, the AP. Of the three agents, tamoxifen given in high dose (5 mg/kg) had the strongest activity, reducing the occurrence of invasive SV carcinomas from 72-83% in controls to 6% (P = 0.0001) and the occurrence of invasive AP carcinomas from 50-72% to 18-22% (P < 0.05).

Androgens↗
PubMed1995

Etoposide, ifosfamide, and cisplatin therapy for refractory childhood solid tumors. Response and toxicity.

BACKGROUND: Etoposide, ifosfamide, and cisplatin (VIP) are each active in treating pediatric solid tumors, and this combination has been shown to be effective in treating adult germ cell tumors. Etoposide, ifosfamide, and cisplatin therapy was used to treat 11 patients, with ages ranging from 14 months to 22 years, with relapsed sarcoma, Wilm's tumor, and hepatoblastoma. METHODS: Etoposide, ifosfamide, and cisplatin therapy was administered daily for 3 days in doses of cisplatin 20 mg/m2 with mannitol 10 g/m2 for 1 hour, etoposide 100 mg/m2, and ifosfamide 1.5 g/m2 with MESNA 360 mg/m2 x 3 doses. A total of 65 courses (range, 3-10/patient) were administered, with 86% of the courses administered at full dose. Hematopoietic growth factors were not used. RESULTS: All 10 evaluable patients responded. Six patients had a complete response (CR) by computed tomographic or magnetic resonance imaging scan after one to three courses. The remaining four patients had a partial response (PR) (> 50% decrease in disease). One PR was converted to a CR by resection of the residual lesions. The major toxicity was myelosuppression. The median nadirs after full doses were as follows: leukocyte count of 900/mm3, absolute neutrophil count (ANC) of 156/mm3, platelet count of 61,000/mm3, and hemoglobin count of 8.6 g/dl; 75% of full dose courses led to an ANC of less than 500. Fever and neutropenia were observed after 8/55 (15%) full dose courses. Two episodes of bacteremia were noted, one with Staphylococcus epidermidis after full recovery of counts. The median time to hematologic recovery was 21 days (range, 14-29 days). No patient developed a decreased creatinine clearance level during therapy. Significant renal solute losses were observed in two patients, both of whom had been pretreated heavily with ifosfamide and had losses before VIP therapy. CONCLUSIONS: Etoposide, ifosfamide, and cisplatin appear to be active in treating childhood solid tumors. This therapy has predictable and tolerable myelotoxicity, and nephrotoxicity does not appear to be more severe than that observed after treatment with ifosfamide alone.

Adolescent↗
PubMed1995

Accuracy of current imaging modalities in the diagnosis of synchronous bilateral Wilms' tumor. A report from the National Wilms Tumor Study Group.

BACKGROUND: Five percent of patients with Wilms' tumor will present with bilateral disease. Recent reports suggest that preoperative imaging studies can exclude contralateral disease reliably, obviating the need for formal surgical exploration of the contralateral kidney. This study was undertaken to determine the accuracy of preoperative imaging in diagnosing bilateral Wilms' tumor. METHODS: The charts of 122 patients with synchronous bilateral Wilms' tumor enrolled in National Wilms Tumor Study-4 were reviewed. With the exception of one child, all had an abdominal computed tomography (CT), ultrasound, or magnetic resonance imaging performed. RESULTS: There were nine patients (7%) in whom the diagnosis of bilaterality was missed by the preoperative imaging studies. All but one of the missed lesions were small, five less than 1 cm and three 1-3 cm. The accuracy of each imaging modality was correlated with tumor size. Computed tomography was more sensitive in detecting bilaterality than ultrasound. However, there was not a single study that was able to detect more than 50% of lesions less than 1 cm in greatest dimension. CONCLUSIONS: This review indicates that even with current advances in imaging technology, synchronous bilateral Wilms' tumor will go unrecognized in 7% of patients if formal exploration of the contralateral kidney is omitted. Although this represents a small percentage of all patients presenting with Wilms' tumor, preoperative diagnosis of bilaterality is essential if parenchymal-sparing procedures are to be performed. Until a more reliable indicator of bilateral disease is found, exploration of the contralateral kidney continues to be recommended.

Child↗
PubMed1995

In situ breast carcinoma after treatment during adolescence for thyroid cancer with radioiodine.

We reviewed the courses of patients treated during childhood or adolescence for thyroid cancer to estimate the frequency of, and to identify possible risk factors for, the occurrence of second malignant tumors in this population. We identified all patients treated for thyroid cancer in a cohort of 1,406 pediatric cancer patients who were diagnosed prior to 20 years of age during the period January 1, 1960 through December 31, 1988 and who were treated at Roswell Park Cancer Institute. Twelve patients were treated for thyroid cancer, of whom nine were women. In situ breast carcinoma was diagnosed 25 and 26 years after diagnosis of thyroid cancer in two of four women treated with radioiodine. No new cancers were diagnosed in the five women treated with thyroidectomy only. Two of four women treated for thyroid cancer during adolescence with radioiodine, which is concentrated in the breast as well as other organs, developed in situ breast carcinoma. Review of a large cohort of adolescent female thyroid cancer patients treated with radioiodine is necessary to provide an accurate estimate of their risk of developing breast cancer. These patients must remain under medical surveillance throughout their lifetimes to facilitate prompt diagnosis of and early intervention for new conditions, such as the occurrence of breast cancer.

Adolescent↗
PubMed1995

A two-filter model for frequency discrimination.

In this paper, we explore a two-filter model, the simplest version of multi-channel models for frequency discrimination of simple tones. According to this model, frequency discrimination is based on a change in the relative output levels of two auditory filters, one centered below and the other above the frequency of the tone. This idea can explain the experimental results that frequency discrimination is relatively unaffected by randomization of stimulus level. Moreover, it suggests a close relationship between the ability of listeners to perform frequency discrimination of simple tones and spectral-shape discrimination of two-tone complexes. The ability of three listeners to perform these two tasks was measured at six frequencies (from 0.25 to 8 kHz). The results from the spectral-shape-discrimination task were used to predict frequency-difference limens. There was a high correlation between obtained and predicted values.

Acoustic Stimulation↗
PubMed1995

Maximum-likelihood procedures and the inattentive observer.

In most experimental situations, it is expected that observers will achieve perfect detection at extremely high signal levels. Technically, it is assumed that the asymptote of the psychometric function is unity. In many practical psychophysical tests, such as those involving children, patients, or nonhuman animals, the observers are occasionally inattentive. Using computer simulations, it was assumed that inattention can be modeled as a stationary stochastic process whose major effect is to produce a psychometric function having an asymptote less than unity. A maximum-likelihood procedure was used to estimate threshold, because it has been shown to provide reasonably stable threshold estimates using very few observations. Inattention increases the variability of the threshold estimate, as would be expected, because inattention reduces the slope of the psychometric function. The simulations also show that the maximum-likelihood procedure poorly estimates the amount of inattention, and can, thereby, produce a strong bias in the threshold estimates, overestimating or underestimating the true values under different circumstances. Inattention appears to affect the two-alternative forced-choice procedure more strongly than the yes-no (go/nogo) procedure.

Attention↗