Biomedical subjects
R B Goldberg
Publications and source records attributed to R B Goldberg.
A novel cell-ablation strategy for studying plant development.
The processes controlling the differentiation of plant cells are not well understood. Two alternative, but not mutually exclusive, mechanisms probably play a major role in plant-cell differentiation. One mechanism utilizes a position-independent, cell-autonomous differentiation process. The other, employs a position-dependent, cell-cell interaction process that requires signals from neighbouring cells. Cell ablation studies can be used to distinguish between these two models of plant-cell differentiation. In this article we outline a new cell-ablation strategy that utilizes promoters with distinct, but overlapping, cell specificities that are fused with cytotoxic and anticytotoxic structural genes. We present preliminary observations on how this strategy can be used to dissect the events controlling anther development.
A preliminary report of the safety and efficacy of fluvastatin for hypercholesterolemia in renal transplant patients receiving cyclosporine.
Hypercholesterolemia is common following renal transplantation and undoubtedly contributes to morbidity and mortality due to occlusive atherosclerosis in these patients. Although 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are more tolerable as low density lipoprotein cholesterol (LDL-C)-lowering agents than other classes of drugs, their use in transplant patients has been limited due to potentially serious interactions with cyclosporine. Fluvastatin is the first wholly synthetic HMG-CoA reductase inhibitor. Because it has a shorter half-life and greater protein-binding capacity than other drugs of this class and has no active circulating metabolites, fluvastatin may be safer than other HMG-CoA reductase inhibitors in this group of patients. To study this question, 19 renal transplant recipients (age, 21-70 years) with hypercholesterolemia (LDL-C > 180 mg/dL; triglycerides < 400 mg/liter) were entered into a 14-week active-treatment period with fluvastatin at 20 mg/day following dietary stabilization and a 3-week placebo washout period. Changes in LDL-C levels were compared with those obtained in control hypercholesterolemic subjects treated in the same way. The lipid-lowering ability of fluvastatin was not imparied in these patients, indicating a lack of interaction with cyclosporine. Mean liver enzyme levels, creatine phosphokinase (CPK), and creatine did not change significantly from baseline. Two subjects experienced myalgias without CPK elevations, and another subject experienced an asymptomatic increase in CPK to > 10 times the upper limit of normal, related to exercise. In conclusion, fluvastatin safely and effectively lowers elevated LDL-C levels in renal transplant recipients.
Female sterile tobacco plants are produced by stigma-specific cell ablation.
We identified a tobacco stigma-specific gene, designated STIG1. The STIG1 gene is developmentally regulated and expressed specifically in the stigmatic secretory zone. We used a chimeric STIG1-GUS gene to show that the stigma-specific STIG1 gene expression pattern is controlled primarily at the transcriptional level. We constructed a stigma-specific cytotoxic gene by fusing the STIG1 gene 5' regulatory region with the coding sequence of the Bacillus amyloliquefaciens barnase gene, to assess the role of the stigmatic secretory zone in the pollination process. Pistils of transgenic STIG1-barnase tobacco plants undergo normal development, but lack the stigmatic secretory zone and are female sterile. Pollen grains germinate on the ablated 'stigmatic' surface, but are unable to penetrate the transmitting tissue of the style. Application of stigmatic exudate from wild-type pistils to the ablated surface increases the efficiency of pollen tube germination and growth and restores the capacity of pollen tubes to penetrate the style. Our data demonstrate the importance of the stigmatic secretory zone in the pollination process and provide an approach to identify compounds produced by the stigma that are critical for successful pollination and fertilization to occur.
Anther development: basic principles and practical applications.
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Plasma lipid levels at diagnosis in type 2 diabetic patients.
Plasma lipid measurements were obtained at the time that 545 subjects were screened for diabetes mellitus. Both the women and men diagnosed with diabetes had significantly higher triglyceride levels (p < 0.05) and lower high-density-lipoprotein cholesterol (HDL-cholesterol) levels (p < 0.05) than those with normal glucose tolerance. Low-density-lipoprotein cholesterol (LDL-cholesterol) levels were only higher in the diabetic women (p < 0.001). Differences in lipid values were diminished somewhat with allowances for the waist-hip ratio. HDL-cholesterol values were inversely related to fasting insulin levels in the normoglycaemic men and women (p < 0.01), but not in the diabetic individuals. Triglyceride levels were strongly positively related to insulin values in the normoglycaemic men and women (p < 0.001 for both), while associations tended to be smaller in the diabetic subjects. In 13 of the diabetic individuals who were not medicated for diabetes over a period of 17.5 +/- 4.6 months, changes in HDL-cholesterol levels were positively related (p = 0.80, < 0.001) and changes in triglyceride levels inversely related (r = -0.70, p < 0.01) to changes in insulin values. These data indicate that at diagnosis Type 2 diabetic patients have an atherogenic lipid pattern that may be related in part to differences in adipose distribution. In addition, the data suggest that HDL-cholesterol is positively related and triglyceride inversely related to insulin action.
A comparison of adiposity measures for screening non-insulin dependent diabetes mellitus.
We compared the accuracies of adiposity distribution measures (waist and hip circumferences, subscapular and triceps skinfold thicknesses, waist-hip and subscapular-triceps ratios) with a measure of adiposity extent (body mass index) for screening non-insulin dependent diabetes mellitus (NIDDM). Of 521 subjects (218 men and 303 women) who had 2 h oral glucose tolerance tests, 43 men and 28 women were found to have NIDDM. Allowing for age, ethnicity, and family history in analyses of covariance, the subscapular skinfold thickness and the ratio of the subscapular to triceps skinfold thicknesses were significantly higher (P < 0.05) in both the men and women found to have diabetes than in their non-diabetic counterparts. The waist-hip ratio was also significantly higher in diabetic women; however, the elevation was not as marked in diabetic men (P = 0.06). The body mass index did not differ between diabetic and non-diabetic men and was only moderately elevated in diabetic women (P = 0.04). Receiver-operator curves were employed to examine the relative accuracies of the body mass index, waist-hip ratio, and subscapular skinfold thickness for screening NIDDM. In both men and women, the waist-hip ratio and subscapular thickness were superior to the body mass index. These data suggest that certain measures of adiposity distribution are more accurate than measures of overall adiposity extent for screening NIDDM and that they may be useful in screening programmes.
Deletions and microdeletions of 22q11.2 in velo-cardio-facial syndrome.
Velo-cardio-facial syndrome (VCFS), an autosomal dominant disorder, is characterized by cleft palate, cardiac defects, learning disabilities and a typical facial appearance. Less frequently, VCFS patients have manifestations of the DiGeorge complex (DGC) including hypocalcemia, hypoplastic or absent lymphoid tissue and T-cell deficiency suggesting that these 2 conditions share a common pathogenesis. Here, we report the results of cytogenetic and molecular studies of 15 VCFS patients. High-resolution banding techniques detected an interstitial deletion of 22q11.21-q11.23 in 3 patients. The remaining 12 patients had apparently normal chromosomes. Molecular analysis with probes from the DiGeorge Chromosome Region (DGCR) within 22q11 detected DNA deletions in 14 of 15 patients. In 2 families, deletions were detected in the affected parent as well as the propositus suggesting that the autosomal dominant transmission of VCFS is due to segregation of a deletion. Deletions of the same loci previously shown to be deleted in patients with DGC explains the overlapping phenotype of VCFS and the DGC and supports the hypothesis that the cause of these two disorders is the same.
Regional and cell-specific gene expression patterns during petal development.
We investigated gene expression patterns that occur during tobacco petal development. Two petal mRNA classes were identified that are present at elevated levels relative to other organs. One class is represented equally in the unpigmented tube and pigmented limb regions of the corolla. The other class accumulates preferentially within the limb region. Limb-specific mRNAs accumulate at different times during corolla development, peak in prevalence prior to flower opening, and are localized in either the epidermal cell layers or the mesophyll. The epidermal- and mesophyll-specific mRNAs change abruptly in concentration within a narrow zone of the limb/tube border. Preferential accumulation of at least one limb-specific mRNA occurs within the corolla upper region early in development prior to limb maturation and pigment accumulation. Limb-specific mRNAs also accumulate preferentially within the unpigmented corolla limb region of Nicotiana sylvestris, a diploid progenitor of tobacco. Runoff transcription studies and experiments with chimeric beta-glucuronidase genes showed that petal gene organ, cell, and region specificities are controlled primarily at the transcriptional level. We conclude that during corolla development transcriptional processes act coordinately on limb-specific genes to regulate their regional expression patterns, but act individually on these genes to define their cell specificities.
A mutant lectin gene is rescued from an insertion element that blocks its expression.
The soybean lectin gene Le1 encodes a prevalent seed protein and is highly regulated during the life cycle. The mutant lectin gene allele le1 is not transcribed detectably, contains a 3.5-kb Tgm1 insertion element within its coding region 0.6 kb 3' to the transcription start site, and leads to a lectinless phenotype. To determine whether the Tgm1 element or a secondary mutation was responsible for repressing le1 gene transcription, we eliminated the insertion element by constructing a chimeric lectin gene (le1/Le1) that contained the 5' half of the le1 gene and its promoter region and the 3' half of the wild-type Le1 gene. Transformed tobacco seed containing the le1/Le1 gene produced both lectin mRNA and protein, demonstrating that the mutant lectin gene control region is transcriptionally competent. By contrast, transformed seed containing the le1 gene produced no detectable lectin mRNA. We conclude that the absence of detectable transcription from the le1 gene is due to transcriptional inhibition by the Tgm1 insertion element and that this element acts at a distance to block transcription from an upstream promoter region.
Sensory function at diagnosis and in early stages of NIDDM in patients detected through screening.
OBJECTIVE: We studied whether sensory function abnormalities are present at diagnosis and whether they develop in the early stages of non-insulin-dependent diabetes (NIDDM). RESEARCH DESIGN AND METHODS: Quantitative assessments of vibration sensitivity at the hallux and index fingers, and thermal sensitivity at the hallux were performed at screening (2-h oral glucose tolerance tests) for diabetes in 364 individuals. Twenty-five subjects diagnosed with NIDDM and 25 matched nondiabetic subjects were restudied after an interval of 12-41 mo. RESULTS: When those with NIDDM (n = 41) or impaired glucose tolerance (IGT) (n = 38) were compared with nondiabetic subjects, there were no significant differences in sensory function indices. However, the vibration threshold and HbA1c were related among those found to be hyperglycemic (IGT and NIDDM combined P less than 0.05; NIDDM alone P less than 0.05). Among diabetic subjects, the vibration threshold and interaction term of height and Hba1c were positively related in a multiple regression analysis (P less than 0.01). There were increments in all sensory thresholds in diabetic patients at follow-up (P less than 0.05 for all). Increments were smaller in control subjects. CONCLUSIONS: These data suggest that although sensory function tends to be normal at diagnosis in NIDDM patients, there appears to be a diminution in sensory function as the disease progresses. An interaction between metabolic factors and height may influence sensory function early in the course of NIDDM.
A soybean embryo cDNA encodes a DNA binding protein with histone and HMG-protein-like domains.
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A plant DNA binding protein shares highly conserved sequence motifs with HMG-box proteins.
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A review of cancer induction by extremely low frequency electromagnetic fields. Is there a plausible mechanism?
A body of epidemiological evidence suggests an association between residential or occupational exposure to extremely low frequency (ELF) electromagnetic fields (EMF) and an increased incidence of cancer in children and adults. Experimental studies at the whole-animal and cellular level are ambiguous; bioeffects suggestive of a carcinogenic effect have been reported, but a similar volume of negative reports can also be assembled. This literature is critically reviewed based on the hypothesis that the epidemiological results are correct, and asking what plausible mechanism could explain a small increase in the incidence of a range of tumors with a non-specific increased exposure to ELF EMF? We focus on four likely mechanisms: 1) disruption of cell communication, 2) modulation of cell growth via changes in calcium ion flux, 3) activation of specific oncogenic gene sequences, and 4) action as a stress factor operating through disruption of hormonal and immune system tumor control mechanisms. We discuss the implications of epidemiologic and experimental results in the context of hypothetical mechanisms of cancer induction, and suggest experiments likely to help define putative EMF hazards.
Engineered male sterility in plants.
We constructed two chimaeric ribonuclease genes that are specifically expressed in anthers of tobacco and rapeseed plants. The expression of these genes affects the production of functional and viable pollen yielding plants that are male sterile. This dominant gene for nuclear male sterility should facilitate the production of hybrid seed in various crops.
Comparison of the lipid profiles of Cubans and other Hispanics with non-Hispanics.
We compared the plasma lipid profiles of Cuban Americans and other Hispanic-American subgroups with those of non-Hispanics. High-density lipoprotein cholesterol levels were lower and triglyceride levels were higher when Hispanic women were compared with non-Hispanic women, and this pattern was also apparent for men. The lower high-density lipoprotein cholesterol and higher triglyceride levels were consistent for both Cuban and non-Cuban Hispanics. There were higher waist-hip ratios and insulin levels in both Hispanic men and women. When allowances were made for these attributes in covariance analyses, the lipid differences were markedly diminished. These data suggest the lower high-density lipoprotein cholesterol and higher triglyceride levels are consistent across Hispanic subgroups and that this lipid pattern may be attributable at least in part to increased insulin resistance in Hispanics.
Congenital myopia in Stickler's hereditary arthro-ophthalmopathy.
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Ocular findings in Treacher Collins syndrome.
We examined 14 patients from nine families referred with the diagnosis of Treacher Collins syndrome. We noted seven significant ocular findings including the following: a subnormal horizontal palpebral fissure length and inferomedial displacement of the lateral canthus in primary gaze; further medial displacement (4.0 mm or more) of the lateral canthus with resultant shortening of the horizontal fissure length on forced eyelid closure (fissure narrowing sign); partial-thickness eyelid colobomata localized to the nasal one half to two thirds of the lower eyelids; bilateral absence of the inferior lacrimal puncta; bilateral blepharoptosis; inferior displacement of the palpebral fissures; and regular astigmatism without any consistent orientation of the axis of astigmatism relative to the lower eyelid defects, blepharoptosis, or lateral canthus. The fissure narrowing sign correlates with known anatomic deficiencies in the Treacher Collins syndrome and may prove valuable in confirming the diagnosis in patients who lack certain typical features.