Biomedical subjects
Publications and source records attributed to Robert Meyer.
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Transforming growth factor-beta (TGF-beta) is a potent immunosuppressant. Overproduction of TGF-beta by tumor cells leads to evasion of host immune surveillance and tumor progression. Results of our early studies showed that adoptive transfer of tumor-reactive, TGF-beta-insensitive CD8(+) T cells into immunocompetent mice was able to eradicate lung metastasis of mouse prostate cancer. The present study was conducted with three objectives. (a) We tested if this technology could be applied to the treatment of solid xenograft tumors in allogeneic immunodeficient hosts. (b) We determined relevant variables in the tumor microenvironment with the treatment. (c) We tested if immune cells other than CD8(+) T cells were required for the antitumor effect. Mouse prostate cancer cells, TRAMP-C2 of the C57BL/6 strain, grown in immunodeficient allogeneic hosts of BALB/c strain, were used as a xenograft model. Tumor-reactive CD8(+) T cells from C57BL/6 mice were isolated, expanded ex vivo, and rendered insensitive to TGF-beta by introducing a dominant-negative TGF-beta type II receptor vector. Seven days following s.c. injection of TRAMP-C2 cells (5 x 10(5)) into the flank of male BALB/c-Rag1(-/-) mice, tumor-reactive, TGF-beta-insensitive CD8(+) T cells (1.5 x 10(7)) were transferred with and without the cotransfer of an equal number of CD8-depleted splenocytes from C57BL/6 donors. Naive CD8(+) T cells or green fluorescent protein-empty vector-transfected tumor-reactive CD8(+) T cells were transferred as controls. Forty days following the transfer, the average tumor weight in animals that received cotransfer of tumor-reactive, TGF-beta-insensitive CD8(+) T cells and CD8-depleted splenocytes was at least 50% less than that in animals of all other groups (P < 0.05). Tumors in animals of the former group showed a massive infiltration of CD8(+) T cells. This was associated with secretion of relevant cytokines, decreased tumor proliferation, reduced angiogenesis, and increased tumor apoptosis. Based on these results, we postulated a concept of antitumor immune response cycle in tumor immunology.
PURPOSE: African-American women have a 2- to 4-fold increased risk of pregnancy-related death compared with Caucasian women. We conducted this study to determine if differences in a combination of socioeconomic and medical risk factors may explain this racial disparity in pregnancy-related death. METHODS: Pregnancy-related deaths of African-American (N=60) and Caucasian (N=47) women were identified from review of pregnancy-associated deaths (N=400) ascertained through cause of death on death certificates, electronic linkage of birth and death files, and review of the hospital discharge database for the State of North Carolina, during the period between 1992 and 1998. Controls (N=3404) were randomly selected from all live births for the same 7-year period. Logistic regression was used to model the association between race and pregnancy-related death. RESULTS: The unadjusted odds ratio (OR) for pregnancy-related death for African-Americans compared with Caucasians was 3.07 (95% confidence interval [CI], 2.08, 4.54). After controlling for gestational age at delivery, maternal age, income, hypertension, and receipt of prenatal care, African-American race remained a significant predictor variable (OR 2.65 [95% CI 1.73, 4.07]). CONCLUSIONS: Our analysis confirms that there is a strong association between race and pregnancy-related death, even after adjusting for potential predictors and confounders.
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OBJECTIVE: To examine the association between health care services variables and pregnancy-related death using a contemporary geographically defined population and enhanced methods for case identification. METHODS: This is a population-based, case-control study from North Carolina for the 7-year period 1992-1998. Pregnancy-related deaths after a live birth (n = 118) were identified after review of pregnancy-associated deaths (n = 400) ascertained from death certificate codes and linkage of birth and death files. Controls (n = 3697) were randomly selected from all registered live births for the same 7-year period and were not matched with cases. This sample size was sufficient to ensure that the standard errors for subgroup prevalences were less than 1%. The associations between pregnancy-related death and health care services were explored with univariate and multivariable regression analysis. RESULTS: Neither maternity care coordination nor nutritional services were protective. There was no association with source of care, private versus public. The adjusted odds ratio (OR) for pregnancy-related death associated with cesarean delivery was 3.9 (95% confidence interval [CI] 2.5, 6.1). The adjusted OR for pregnancy-related death associated with the receipt of prenatal care was 0.2 (95% CI 0.1, 0.6). CONCLUSION: Removing barriers to and actively promoting use of prenatal care services and decreasing the rate of cesarean deliveries could decrease the number of pregnancy-related deaths.
OBJECTIVE: Gastroschisis is a congenital anomaly that has been reported to be increasing in frequency. The objective of this study was to determine the birth prevalence of gastroschisis using two large databases. STUDY DESIGN: We reviewed data from a statewide database and a national database from a neonatal health care provider, abstracting cases of gastroschisis. RESULTS: In North Carolina, the birth prevalence of gastroschisis increased from 1.96 per 10,000 births in 1997 to 4.49 per 10,000 births in 2000 (p=0.0007). The overall increase was almost entirely because of the increase in infants born to mothers less than 20 years old. Among infants receiving care from the national neonatal provider, the prevalence of gastroschisis increased from 2.9 per 1000 patients in 1997 to five per 1000 patients in 2001 (p=0.044). CONCLUSION: The birth prevalence of gastroschisis is increasing in North Carolina, and this trend may be occurring nationally. The rapid change in the birth prevalence in the subset of population most at risk for gastroschisis implicates environmental or pharmacologic teratogens rather than changing population characteristics as a causal factor in the development of gastroschisis.
Medial-to-lateral somatotopy is a well-established feature of the human primary somatosensory cortex (SI); however, it is unknown whether, similarly to non-human primates, a rostral-to-caudal somatotopic arrangement exists as well. Therefore, in this functional magnetic resonance imaging (fMRI) study on eight healthy human subjects, five circumscribed skin areas sequentially located on the third finger and the palm of the hand were stimulated with innocuous electrical pulses. Within area 3b of contralateral SI, successive cortical representation sites ordered in a rostral-to-caudal fashion were seen in the group analysis and in six individual subjects. The fingertip was located most rostrally, whereas the proximal parts of the finger as well as the distal palm were represented at more caudal locations. Within area 1, the group analysis revealed a similar pattern of discrete representations. However, in contrast to area 3b, the fingertip was located most caudally, whereas the more proximal parts of the finger were found to be represented rostrally within area 1. Thus, the representation pattern of area 1 appeared as a 'mirror image' of that of area 3b. In comparison to the representations of the finger and the distal palm, the proximal palm was found to be represented at a more medial position of the postcentral gyrus.
The use of pharmacogenetics and pharmacogenomics in the drug development process, and in the assessment of such data submitted to regulatory agencies by industry, has generated significant enthusiasm as well as important reservations within the scientific and medical communities. This situation has arisen because of the increasing number of exploratory and confirmatory investigations into variations in RNA expression patterns and DNA sequences being conducted in the preclinical and clinical phases of drug development, and the uncertainty surrounding the acceptance of these data by regulatory agencies. This report summarizes the outcome of a workshop cosponsored by the Food and Drug Administration (FDA), the Pharmacogenetics Working Group (PWG), the Pharmaceutical Research and Manufacturers of America (PhRMA), and the PhRMA Preclinical Safety Committee (DruSafe). The specific aim of the workshop was to identify key issues associated with the application of pharmacogenetics and pharmacogenomics, including the feasibility of a regulatory "safe harbor" for exploratory genome-based data, and to provide a forum for industry-regulatory agency dialogue on these important issues.
Evaluations of government-funded training programs often combine results from similar operations in multiple sites. Findings inevitably vary. It is common to relate site-to-site variations in outcomes to variations in program design, participant characteristics, and the local environment. Frequently, such connections are constructed in a narrative synthesis of multisite results. This article uses findings from the evaluations of California's Greater Avenues for Independence (GAIN) program and the National Evaluation of Welfare-to-Work Strategies (NEWWS) to illustrate why it is important to question the legitimacy of such syntheses. The discussion is carried out using a simple multilevel evaluation model that incorporates models of both individual outcomes within sites and variation in program effects across sites. The results indicate that tempting generalizations about GAIN and NEWWS effects are statistically unjustified but that significant progress might be made in identifying the determinants of program effects in future demonstrations with some changes in evaluation strategy.
Cortical signal intensity changes due to brief (1 s) innocuous electrical stimuli applied to the second and fifth finger of the right hand were measured by means of fMRI at 1.5 T. The activation pattern in this event-related fMRI approach closely resembled that obtained in recent block-design studies. Activations were found in contralateral primary (SI) and bilaterally in secondary (SII) somato-sensory cortex as well as in posterior parietal cortex, insula, and supplementary motor area (SMA). In SI, the somatotopic organization of the hand area is demonstrated, more clearly to be seen in area 3b than in area 1 and 2. In conclusion, the feasibility to employ event-related somatosensory stimulation paradigms in fMRI studies is demonstrated.