Managing potential conflicts in community health improvement: an interview with Elliott Fisher. Interview by Maggie Kennedy.
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Community Health Planning↗
Biomedical subjects
E Fisher
Publications and source records attributed to E Fisher.
Stage-specific oligonucleotide uptake in murine bone marrow B-cell precursors.
Fluorescein isothiocyanate (FITC)-conjugated phosphodiester and phosphorothioate oligonucleotides were used in four-color flow cytometry with murine bone marrow cells stained with monoclonal antibody specific for the differentiation markers B220, S7 (CD43), and BP-1 to show possible stage-specific oligonucleotide uptake. Relatively low uptake was observed among pre-Pro- and early Pro-B cells. Late Pro-B- and pre-B cells had increased oligonucleotide uptake, whereas B cells had a lower level. Cell membrane binding of oligonucleotides varied during B-cell differentiation in parallel with internalization, which was documented by confocal microscopy. An FITC-conjugated polyanionic dextran sulfate also showed differentiation-related B-cell association, suggesting the presence of cell membrane binding sites specific for polyanions as opposed to a unique feature of the DNA backbone. Interpretation of antisense experiments in murine bone marrow cells will need to account for the heterogeneous oligonucleotide uptake among differentiating B cells.
Animals↗
Human haploinsufficiency--one for sorrow, two for joy.
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Abnormalities, Multiple↗
Inhibition of T4 polynucleotide kinase activity by phosphorothioate and chimeric oligodeoxynucleotides.
Whole and partially modified phosphorothioate oligodeoxynucleotides (ODN) were found to directly inhibit T4 polynucleotide kinase (PNK) activity, while phosphodiester ODN showed no detectable inhibition. This inhibition was found to be length dependent, as demonstrated by a 28-mer phosphorothioate ODN with an IC50 of 12 nM, and an 8-mer phosphorothioate ODN with an IC50 of 27,000 nM. Inhibition depended on the number and type of modified internucleotide linkages: a 20-mer phosphorothioate ODN had an IC50 of 21 nM, while a chimeric ODN with seven phosphorothioate linkages and an identical sequence showed no inhibition. On the other hand, the same sequence as a chimeric phosphorodithioate ODN (with seven dithioate linkages) had an IC50 of 580 nM. Four different chimeric phosphorodithioate ODN showed markedly different potencies of inhibition, suggesting that inhibition of PNK activity can be sequence specific.
Bacteriophage T4↗
Racial differences in fracture risk.
Blacks appear to have a lower risk of fractures than whites, but there has been little research regarding racial differences in the risk of fractures at sites other than the hip. We used Medicare claims to investigate the risks of fractures of the hip, distal forearm, proximal humerus, and ankle among American whites and blacks over 65 years old. Each of these fractures occurred more frequently in women than in men and (except for ankle fracture) displayed an increase in risk with age. Blacks had a lower risk than whites, although these differences were smaller for fractures of the ankle and were less pronounced among men. The most likely explanation for this is a constitutional or metabolic factor prevalent in blacks that particularly influences the risk of osteoporotic fractures in women.
Aged↗
Calcium-binding properties of SSP-5, the Streptococcus gordonii M5 receptor for salivary agglutinin.
Streptococcus gordonii M5 expresses a lectin on its surface (SSP-5) which binds to human salivary agglutinin (SAG). This interaction requires sialic acid residues of SAG and divalent cations and may mediate the colonization of oral tissues by this organism. In this report, we show that the binding of SAG to SSP-5 requires calcium and that SSP-5 is a high-affinity calcium-binding protein. SAG-mediated aggregation of S. gordonii M5 was inhibited by 1 mM EDTA, and the restoration of aggregation occurred only upon the readdition of calcium. To ascertain the level at which calcium exerts its effects, the calcium-binding properties of SSP-5 were evaluated by using a 45Ca binding assay. In addition, a kinetic analysis of calcium binding was carried out by using fura2, a fluorescent calcium-binding dye. These analyses showed that SSP-5 is a high-affinity calcium-binding protein that binds 1 mol of calcium per mol of protein and has a dissociation constant of 0.45 +/- 0.2 microM. The calcium-binding capacity of SSP-5 was also calculated independently to be 1.0 +/- 0.2 mol of Ca per mol of SSP-5 by column chromatography on Sephadex G-25 equilibrated with 10 microM 45Ca. To localize the calcium binding site of SSP-5, a series of C-terminal deletion mutants were expressed in Escherichia coli and evaluated for calcium-binding activity. Deletion of the 250 C-terminal residues of SSP-5 had little effect on calcium binding. However, deletion of residues 1168 to 1250 resulted in the loss of calcium-binding activity, suggesting that this region is important for calcium binding by SSP-5.
Adhesins, Bacterial↗
A comparative evaluation of cognitive-behavioral therapy (CBT) versus exercise therapy (ET) for the treatment of body image disturbance. Preliminary findings.
Cognitive-behavioral therapy (CBT) was compared to a combination of aerobic/anaerobic exercise therapy (ET) for the treatment of elevated levels of body image disturbance in college females. CBT consisted of a modification of the 1987 Butters and Cash procedure that was tailored for group intervention; ET consisted of weightlifting and aerobic dancing. Using a counterbalancing procedure, the same therapists conducted both 6-week interventions, which were compared to a nontreated control group. Results revealed equivalent reductions for both treatment groups when compared to controls on measures of body image disturbance reflective of trait and state body weight anxiety, cognitive-behavioral aspects of appearance, and overall body dissatisfaction. Unfortunately, few subjects were available for follow-up analyses, preventing an evaluation of the stability of changes. The findings are discussed with regard to the potential role of fitness training as an adjunct to cognitive-behavioral interventions for body image disturbance.
Adult↗
Lumpectomy compared with lumpectomy and radiation therapy for the treatment of intraductal breast cancer.
BACKGROUND AND METHODS: Women with ductal carcinoma in situ have been treated both by lumpectomy and by lumpectomy followed by radiation therapy, but the benefit of combined therapy is uncertain. A group of 818 women with ductal carcinoma in situ were randomly assigned to undergo lumpectomy or lumpectomy followed by breast irradiation (50 Gy). Sufficient tissue was removed that the margins of the resected specimens were histologically tumor-free. The mean duration of follow-up was 43 months (range, 11 to 86). The principal end point of the study was event-free survival, as defined by the presence of no new ipsilateral or contralateral breast cancers, regional or distant metastases, or other cancers and by no deaths from causes other than cancer. RESULTS: Five-year event-free survival was better in the women who received breast irradiation (84.4 percent, vs. 73.8 percent for the women treated by lumpectomy alone; P = 0.001). The improvement was due to a reduction in the occurrence of second ipsilateral breast cancers; the incidence of each of the other events was similar in the two groups. Of 391 women treated by lumpectomy alone, ipsilateral breast cancer developed in 64 (16.4 percent); it was noninvasive in 32 and invasive in the remaining 32. Of 399 women treated with lumpectomy and breast irradiation, ipsilateral breast cancer developed in 28 (7.0 percent) (noninvasive in 20 and invasive in 8). The five-year cumulative incidence of second cancers in the ipsilateral breast was reduced by irradiation from 10.4 percent to 7.5 percent for noninvasive cancers and from 10.5 percent to 2.9 percent for invasive cancers (P = 0.055 and P < 0.001, respectively). CONCLUSIONS: Breast irradiation after lumpectomy is more appropriate than lumpectomy alone for women with localized ductal carcinoma in situ.
Breast Neoplasms↗
Characterization of the gene for apolipoprotein E5-Frankfurt (Gln81->Lys, Cys112->Arg) by polymerase chain reaction, restriction isotyping, and temperature gradient gel electrophoresis.
A new apolipoprotein (apo) E variant, apoE5-Frankfurt, was identified in a 43-year-old male with moderate hypercholesterolemia. On isoelectric focusing in an immobilized pH gradient, apoE5-Frankfurt migrated to a position more cathodic than apoE4 (Cys112->Arg). On sodium dodecyl sulfate-gel electrophoresis, its apparent molecular weight could not be distinguished from that of the three common apoE isoforms (E2, E3 and E4). Restriction isotyping with CfoI (HhaI) showed that apoE5-Frankfurt had arginine in positions 112 and 158 of the mature protein, suggesting that the mutation accounting for the additional positive charge had occurred in an epsilon 4 allele. The third and the fourth exon of the apoE gene were amplified using the polymerase chain reaction and analyzed by temperature gradient gel electrophoresis. This suggested that there were two mutations in the fourth exon of the mutant allele. Cloning and sequencing disclosed that, apart from the exchange of arginine for cysteine in position 112, a C to A substitution replaced glutamine (CAA) in position 81 by lysine (AAA).
Adult↗
Typing of the 3' hypervariable region of the apolipoprotein B gene: approaches, pitfalls, and applications.
Apolipoprotein B-100 is the principal protein component of lipoproteins with very low, intermediate, and low density. The interaction of apoB-100 with low density lipoprotein (LDL) receptors is responsible for the uptake of LDL into cells. An AT-rich hypervariable region is located adjacent to the 3' end of the apoB gene. It consists of a variable number of tandemly repeated sequences (VNTR). Two approaches were used to analyze this polymorphism. In both, the region harboring the VNTR was amplified with the polymerase chain reaction (PCR). In the first method, fluorescently labeled primers were used in the PCR reactions and products were separated in agarose gels by means of an automated fluorescent fragment analyzer. In the second method, PCR products were analyzed in denaturing polyacrylamide gels and detected with silver staining. Even in the highly sophisticated automated system, agarose gel electrophoresis did not always enable unequivocal assignment of VNTR alleles. In contrast, denaturing polyacrylamide gel electrophoresis made it possible to distinguish the 15 bp differences between the VNTR alleles in a precise and simple manner. The VNTR polymorphism was typed in 234 individuals. Among these were 136 patients with coronary artery disease and 74 healthy controls. Thirteen alleles could be distinguished. The allele containing 49 repeats (VNTR-49) was found in 9.2% of the coronary artery disease patients and in 4.7% of the controls. Thus, the VNTR-49 allele increases relative coronary risk by about twofold. It is concluded that the apoB VNTR polymorphism is a potentially useful genetic marker. Since agarose gel electrophoresis may lead to ambiguous results, we prefer typing by denaturing polyacrylamide gel electrophoresis.(ABSTRACT TRUNCATED AT 250 WORDS)
Alleles↗
Comparison of cellular binding and uptake of antisense phosphodiester, phosphorothioate, and mixed phosphorothioate and methylphosphonate oligonucleotides.
The effects of phosphorothioate (S-oligonucleotide) or terminal phosphorothioate-phosphodiester (S-O-oligonucleotides) or methylphosphonate-phosphodiester (MP-O-oligonucleotides) modifications on mouse spleen cell surface binding, uptake, and degradation were studied using fluorescein (FITC)-conjugated oligonucleotides. S-oligonucleotides had the highest cell binding and uptake, followed by S-O-, O-, and MP-O-oligonucleotides. Competition studies indicated that S-oligonucleotides have an increased affinity for cell membrane oligonucleotide binding sites, because they could completely block O-oligonucleotide binding at a molar ratio of just 0.1. Uptake of all oligonucleotides was higher in B cells than T cells and was increased by stimulation with the B-cell mitogen, lipopolysaccharide. Although our cells had been purified using conventional techniques to eliminate dead cells, there remained about 5% of cells that were dead or dying, as determined by flow cytometry using propidium iodide staining. Of note, oligonucleotide association with dead cells was approximately 50-fold greater than that with living cells. Confocal microscopy confirmed that the oligonucleotides in living cells were intracellular, and indicated little nuclear uptake by 4 h. While extensive degradation of intracellular O-oligonucleotides was apparent by 4 h, there was no detectable degradation of S-, S-O, or MP-O-oligonucleotides.
Animals↗
An animal model for pharyngocutaneous fistulas.
Postoperative pharyngocutaneous fistula is not an uncommon complication. Although the frequency of postoperative fistulae has decreased with the use of perioperative broad-spectrum antibiotics, it remains a complication with significant morbidity and expense. We present an animal model for postoperative pharyngocutaneous fistulae based on increasing wound tension. The New Zealand white rabbit was used to assess the rate of wound breakdown in the thyrohyoid membrane. The animals were assigned to one of seven groups according to the width of tissue resected. After tissue resection, the pharyngeal wounds were repaired, as were the overlying skin wounds. Animals were monitored postoperatively up to 14 days, at which time they were killed and underwent autopsy. Statistically significant results were achieved that demonstrate an increasing incidence of pharyngeal wound breakdown associated with increasing width of tissue resected and, therefore, closure tension. The procedure and results will be presented in detail. We propose that this model may be used to assess postoperative wounds as well as substances or methods touted as promoters of wound healing.
Animals↗
Registration of dental radiographs using projective geometry.
Dunn and van der Stelt recently introduced a new model of radiographic image registration which makes use of the correspondence of 3D structures (Dunn SM, van der Stelt P. Dentomaxillofac Radiol 1992; 21: 142-7; Dunn SM et al. Dentomaxillofac Radiol 1993; 22: 77-80). Using a synthetic projective geometry, an algorithm was developed that utilized five-point projective invariants to describe the relative location of each image pixel. A limitation of this synthetic approach is that there will always be a single line passing through the image that cannot be registered. In this paper, an algorithm which is based upon an analytical projective geometry is introduced. This algorithm describes each image pixel by using a coordinate system called a reference triangle. It was shown experimentally that this algorithm successfully registers the entire image. It can also perform the registration almost six times faster than the original algorithm.
Algorithms↗
New nonpeptide angiotensin II receptor antagonists. 2. Synthesis, biological properties, and structure-activity relationships of 2-alkyl-4-(biphenylylmethoxy)quinoline derivatives.
A novel series of nonpeptidic angiotensin II (AII) receptor antagonists is reported, derived from linkage of the biphenylcarboxylic acid or biphenylyltetrazole moiety found in previously described antagonists via a methyleneoxy chain to the 4-position of a 2-alkyl quinoline. When evaluated in an in vitro binding assay using a guinea pig adrenal membrane preparation, compounds in this series generally gave IC50 values in the range 0.01-1 microM. Structure-activity studies showed the quinoline nitrogen atom and a short alkyl chain at the quinoline 2-position to be essential for receptor binding. On intravenous administration in a normotensive rat model, the more potent compounds inhibited the AII-induced pressor response with ED50 values in the range 0.1-2.0 mg/kg. One of the compounds, 2-ethyl-4-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methoxy]quinoline (5g), demonstrated good oral activity in two rat models. At doses in the range 1-10 mg/kg in AII-infused, normotensive rats, the compound exhibited a dose-related inhibition of the pressor response with a good duration of action at the higher doses. In a renal hypertensive rat model, compound 5g showed a rapid and sustained lowering of blood pressure at a dose of 5 mg/kg. On the basis of its profile, this compound, designated ICI D8731, has been selected for clinical evaluation.
Angiotensin II↗
Racial differences in social support and mental health in men with HIV infection: a pilot study.
The mediating role of social support in the mental health and behaviours of persons coping with life-threatening chronic illness is of potentially great importance in determining the quality of life of persons with HIV infection (PWHs). As part of a biracial pilot study of the ways black and white men manage the stresses of sexually acquired HIV infection, we have examined the relationship between social support and mental health and behaviours. Forty homosexual/bisexual men (20 white and 20 black) attending a Detroit hospital-based HIV outpatient clinic were recruited for the study and underwent physical and mental health (HSCL-59 and NIMH DIS interview), behavioural and psychosocial evaluations, and a neuropsychologic screening test battery. The black and white men did not differ in terms of age, education, sexual behaviours, physical or mental health status. However, the black men were less likely to be open about their sexuality to their primary social support network, and to report that their social support was less affirmative than did the white men. When correlations between the six-dimensional social support measures (Wortman & O'Brien, 1987) and HSC-L distress scores were examined, both availability of material social support and affirmation were correlated negatively with distress among the white men but positively among the black men. Similarly, the previously observed positive relationship between perceived adequacy of social support and adoption of safer sexual practices was observed among white but not black participants.(ABSTRACT TRUNCATED AT 250 WORDS)
Adaptation, Psychological↗
Changes in hepatic glutathione metabolism in diabetes.
Glutathione is important in the regulation of the redox state, and a decline in its tissue level has often been considered to be indicative of increased oxidative stress in diabetes. In this study of diabetic rats, the level of hepatic glutathione was normal unless food intake was restricted. Thus, the previous report of a reduction in hepatic glutathione in diabetes is likely to be the result of food deprivation rather than diabetes alone. In contrast to changes characteristic of oxidative stress, the efflux of glutathione in bile from diabetic animals was significantly decreased, whereas hepatic mixed disulfides were unchanged, and the hepatic gamma-glutamyltransferase activity was considerably increased. These changes were not reproduced by food deprivation. The decrease in biliary excretion of glutathione in diabetes may reflect an attempt to conserve glutathione by activation of the hepatic gamma-glutamyl cycle. We conclude that the disturbances of glutathione metabolism in diabetes are not typical of those seen in oxidative stress or food restriction.
Animals↗
Interaction of ascorbic acid and glucose on production of collagen and proteoglycan by fibroblasts.
Collagen and proteoglycans are two major constituents of the extracellular matrix, and their abnormalities have been incriminated in the pathogenesis of diabetic complications. A decrease of plasma ascorbic acid has been reported in diabetes and thus may play a role in the collagen and proteoglycan abnormalities in diabetes. Ascorbic acid and glucose share structural similarity, and their metabolism may interact at the level of membrane transport and cellular action. In this study, we used a fibroblast culture system to explore this possibility. Ascorbic acid increased collagen and proteoglycan both in the culture medium and the cell layer. This stimulatory action of ascorbic acid was inhibited by the presence of glucose at a concentration of 25 mM. The effect of high glucose concentration was not mediated by inhibition of ascorbic acid uptake by fibroblasts. Insulin is able to abolish this inhibitory action of glucose on collagen production, but the precise mechanism is unclear. These results show that the high glucose concentration in diabetes can impair the action of ascorbic acid at the cellular level. This may further accentuate the problem of decreased availability of this vitamin as a result of its low plasma concentration.
Amino Acids↗
Abnormalities of ascorbic acid metabolism and diabetic control: differences between diabetic patients and diabetic rats.
Ascorbic acid is required in the synthesis of collagen and is also an important anti-oxidant. In a previous study, plasma ascorbic acid concentration was found to be decreased in diabetic patients but there was no relationship with blood glucose level. In the current study of diabetic patients, both plasma ascorbic acid and its urinary excretion correlated inversely with glycosylated hemoglobin level. Plasma ascorbic acid was also lower in diabetic rats but urinary ascorbic acid was elevated. The divergent trend in urinary ascorbic acid excretion observed in diabetic patients and diabetic rats may be due to difference in the ability of these two species to synthesize ascorbic acid. Difference in renal reabsorption of ascorbic acid may also be a relevant factor. The lower plasma and urinary ascorbic acid levels in diabetic patients with more severe hyperglycaemia indicates that this group of patients is particularly at risk of developing deficiency of this vitamin. As ascorbic acid has many important functions in the body, it may be necessary to supplement this vitamin in patients with chronically poorly controlled diabetes.
Adult↗