Biomedical subjects
R W Miller
Publications and source records attributed to R W Miller.
Special susceptibility of the child to certain radiation-induced cancers.
The carcinogenic effects of exposure to ionizing radiation vary markedly with age, as revealed by studies of Japanese atomic bomb survivors and of Marshall Islanders exposed to fallout from U.S. nuclear weapons tests in the South Pacific in 1954. An increase in cancers of adulthood after intrauterine exposure, as reported in 1988, has not been sustained. After childhood exposure, increases in leukemia, breast cancer, and thyroid cancer are well established. The carcinogenic effects of radiation on the young have been reported after intrauterine exposures and after exposures during childhood. Cancers with short latent periods such as leukemia occur during childhood, but those with long latent periods such as breast cancer occur in adulthood.
Delayed effects of external radiation exposure: a brief history.
Within months of Roentgen's discovery of X rays, severe adverse effects were reported, but not well publicized. As a result, over the next two decades, fluoroscope operators suffered lethal skin carcinomas. Later, case reports appeared concerning leukemia in radiation workers, and infants born with severe mental retardation after their mothers had been given pelvic radiotherapy early in pregnancy. Fluoroscopy and radiotherapy for benign disorders continued to be used with abandon until authoritative reports were published on the adverse effects of ionizing radiation by the U.S. NAS-NRC and the UK MRC in 1956. Meanwhile, exposure to the atomic bombs in Japan had occurred and epidemics of delayed effects began to be recognized among the survivors: cataracts (1949), leukemia (1952) and severe mental retardation among newborn infants after intrauterine exposure (1952). No statistically significant excess of germ-cell genetic effects was detected by six clinical measurements (1956), the F1 mortality (1981), cytogenetic studies (1987) or biochemical genetic studies (1988). Somatic cell effects were revealed by long-lasting chromosomal aberrations in peripheral lymphocytes (1968), and somatic cell mutations were found at the glycophorin A locus in erythrocytes (1992). Molecular biology is a likely focus of new studies based on the function of the gene for ataxia telangiectasia (1995), a disorder in which children have severe, even lethal acute radiation reactions when given conventional doses of radiotherapy for lymphoma, to which they are prone. Also, obligate heterozygote female relatives can be studied for increased susceptibility to radiation-induced breast cancer, as suggested by clinical studies. The tumor registries in Hiroshima and Nagasaki now provide incidence data that show the extent of increases in eight common cancers and no increase in eight others (1994). The possibility of very late effects of A-bomb exposure is suggested by recent reports of increased frequencies of hyperparathyroidism, parathyroid cancers and certain causes of death other than cancer.
T cells which do not express membrane tumor necrosis factor-alpha activate macrophage effector function by cell contact-dependent signaling of macrophage tumor necrosis factor-alpha production.
Previous studies have suggested that T cell contact-dependent signaling of macrophages (Mphi) is mediated by membrane tumor necrosis factor-alpha (memTNF-alpha), based on the observation that anti-TNF-alpha could inhibit T cell-mediated Mphi activation. The current report confirms that anti-TNF-alpha does inhibit activation of interferon-gamma (IFN-gamma)-primed Mphi by paraformaldehyde-fixed activated T cells. However, the involvement of membrane molecules other than memTNF-alpha in the contact-dependent signaling is suggested by two lines of evidence. First, the TH2 clone, AK8, displayed neither secreted TNF-alpha/beta nor memTNF-alpha/beta detectable by bioassay or immunofluorescence. Nonetheless, AK8 cells were equally effective, on a per cell basis, in contact-dependent signaling of M phi activation as TH2 and TH1 cells which do express memTNF-alpha. Second, the expression of memTNF-alpha by the TH2 clone, D10.G4, is maximal 24 h after activation, whereas the ability of this clone to activate Mphi is maximal at 6-8 of activation and declines thereafter. Since TNF-alpha is known to play a critical role in activation of Mphi effector function, it was hypothesized that T cell membrane components other than memTNF-alpha might signal Mphi production of TNF-alpha, thus allowing autocrine TNF-alpha stimulation of Mphi effector function. In support of this, it is demonstrated that paraformaldehyde-fixed activated TH2 cells can induce de novo production and release of TNF-alpha by Mphi. This effect was not an artifactual result of paraformaldehyde fixation since paraformaldehyde-fixed resting T cells did not induce TNF-alpha gene expression. Previous studies have demonstrated a role for autocrine TNF-alpha stimulation in LPS induction of effector function in recombinant IFN-gamma-primed Mphi. The current study confirms that TNF-alpha plays a critical role in T cell contact-dependent signaling of Mphi but indicates that memTNF on the T cells may not be a sine qua non factor for contact-dependent signaling. The data suggest that other T cell membrane molecules contribute to activation of Mphi effector function by stimulation of M phi TNF-alpha production.
Evaluation of commercial immunoassays for the detection of alachlor in milk, eggs and liver.
For regulatory purposes, there is a need for rapid, uncomplicated, and inexpensive methods to monitor pesticide residues in food. Commercial immunoassay kits from 3 manufacturers were evaluated for the detection of alachlor in cow milk and urine, and one kit was chosen for assay of chicken eggs and livers. Milk and urine were analyzed after a 1:2 dilution in water, and a rapid extraction procedure was developed for eggs and liver samples. Assays of incurred samples were performed after dosing a cow and several chickens with alachlor. Alachlor was detected in milk and eggs, but not in livers from hens dosed up to 12 mg/kg body weight. The ELISA detection limits were 0.3 ng/mL in milk, 2 ng/g in eggs, and 3 ng/g in liver. The major drawback with the kits was the low cross-reactivity of the antibodies for some of the alachlor metabolites.
Targeting cancer control: the state cancer control map and data program.
The State Cancer Control Map and Data Program (National Technical Information Service, Springfield, Va) allows state and county mortality maps and data tables to be tailored according to the user's choice of cancer site, age, gender, race, county, and time period between 1953 and 1987. Counties and subpopulations within these maps and data tables that are identified as having exceptionally high rates of specific cancers can then be targeted for early detection or primary prevention. These maps and data tables provide a means for focusing state, local, and individual efforts to reduce cancer mortality in appropriate populations in areas with high mortality rates.
Energy transduction by nitrogenase: binding of MgADP to the MoFe protein is dependent on the oxidation state of the iron-sulphur 'P' clusters.
Hydrolysis of MgATP to MgADP is essential for nitrogenase action. There is good evidence for binding of both nucleotides to the Fe protein of nitrogenase, but data indicating their binding to the MoFe protein have been controversial [see Miller and Eady (1989) Biochem. J. 263, 725-729]. The binding of MgADP to the MoFe protein of nitrogenase of Klebsiella pneumoniae was investigated by non-equilibrium gel-filtration column methods. No binding of MgADP to the dithionite-reduced protein could be detected. Treatment of the MoFe protein with phenosafranine [midpoint potential (Em) -270 mV] did not affect the activity, and oxidized the 'P' clusters but not the iron-molybdenum cofactor (FeMoco) centres. This oxidized species bound 3.9 mol of MgADP with a binding pattern characteristic of low rates of ligand dissociation. These observations suggest that the variability in published data on nucleotide binding to the MoFe protein is related to poor control of the protein oxidation level. Our data, coupled with the observation that 'P' clusters become oxidized during reduction of N2 [Lowe, Fisher and Thorneley (1993) Biochem. J., in the press], led us to propose that the ADP binding sites are transiently filled during enzyme turnover by hydrolysis of ATP originally bound to the Fe protein, and that hydrolysis occurs on a bridging site on the MoFe-Fe-protein complex.
The nitrogenase proteins of Rhizobium meliloti: purification and properties of the MoFe and Fe components.
The alfalfa-Rhizobium meliloti symbiosis contributes a major portion of biologically fixed nitrogen to temperate zone forage crop production. Highly-purified molybdenum-iron (MoFe) and iron (Fe) nitrogenase components were obtained for the first time from extracts of R. meliloti bacteroids. Intact bacteroid cells were isolated anaerobically from 100 g quantities of alfalfa nodules following storage in liquid nitrogen. Centrifuged bacteroid extracts showed a marked reduction in specific activity when assayed at protein concentrations less than 1 mg/ml. Both nitrogenase proteins were resolved and purified to homogeneity as determined spectroscopically and by SDS-PAGE. The purified MoFe protein differed in several respects from previously characterized nitrogenase proteins. Saturation of the acetylene-reducing and proton-reducing activities of the R. meliloti MoFe protein required higher relative concentrations of Fe protein than nitrogenase proteins purified from free living diazotrophs. Electron allocation to dinitrogen reduction was sustained at component ratios similar to those present in bacteroid extracts, suggesting that while the observed saturation effects were not detrimental to physiological function in the symbiotic system, overall activity could be enhanced by higher levels of iron protein. Analyses of the MoFe protein gave 22 Fe, 22 labile sulfide and 1.7 Mo atoms per molecular unit of 215 kDa. Dithionite-reduced MoFe protein contained a spin 3/2 iron centre but had a lower visible absorbance at 360 nm than the equivalent Azotobacter chroococcum component. Amino-acid composition indicated a notably lesser tryptophan content, and cysteine content greater than that of the equivalent tetrameric protein of free living diazotrophs. Ratios of acidic and basic residues were similar to other MoFe proteins. Calculation of hydrophobicity and discriminant parameters gave values midway between those expected for soluble cytoplasmic proteins and peripheral membrane associated proteins. ADP was tightly bound by the dithionite-free MoFe protein containing reduced iron-molybdenum cofactor. The R. meliloti iron protein was found to be a 64 kDa homodimer containing a single 4Fe-4S metal centre.
Digestive-tract cancer in cystic fibrosis.
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In memoriam Louis H. Hempelmann (1914-1993). An appreciation.
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Risk of breast cancer in ataxia-telangiectasia.
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Childhood leukemia and neonatal exposure to lighting in nurseries.
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Bronchiectasis in children with lymphocytic interstitial pneumonia and acquired immune deficiency syndrome. Plain film and CT observations.
In a review of 77 HIV positive children seen between 1981 and 1990, 32 were diagnosed as having lymphocytic interstitial pneumonitis). Four of the LIP group developed bronchiectasis, a finding not previously reported. The precise factors leading to the bronchiectasis are unclear. All patients had chronically consolidated lung with volume loss. A history of recurrent bacterial superinfection was not noted in any of the cases. With more cases of HIV positive children living longer, bronchiectasis, long known to occur in primary immunologic disorders, will probably be more frequently noted.
A simple CT aperture emulator for use with a radiotherapy simulator.
Tumor localization in radiation treatment planning often involves the generation of quantitative anatomical data from multiple imaging modalities. It is desirable to take all of the images in the selected treatment position, which is usually decided upon during the initial simulator session. The different scanning modalities are often operated by different staff, at different times and in different locations; thus, it is difficult to ensure consistency in the position of the patient's body, and its documentation, at various times and places. Also, devices such as CT and MR scanners frequently pose restrictions due to their limited apertures. Failure to consider the physical limitations of such scanning equipment at the time of simulation or localization may result in placing the patient in a treatment position which will not fit through the aperture of the CT (or MRI) scanner, or which will result in a clinically important portion of the anatomy being "cut off" in the resulting scans. This can lead to re-simulation of the patient or result in a lack of accurate coordination of simulator and CT scan data. To minimize problems such as these, we have developed a CT Aperture Emulator which can be used at the time of the initial simulation. This is a lightweight "halo" easily attached to the simulator, which mimics the size and shape of the CT aperture. It permits reproducible adjustment of the patient's position, while allowing technologists and physicians to set up the patient with respect to potential CT constraints, in particular with regard to the use of immobilization and support devices. The emulator device also facilitates reproducing a patient's treatment position on the CT scanner. The concept has been found to have additional clinical uses and can be extended to a variety of imaging equipment.
A Hox 3.3-lacZ transgene expressed in developing limbs.
We describe transgenic mouse lines that express lacZ under the control of the Hox 3.3 Promoter II. The correct anterior boundary can be fixed by 3.6 kb of promoter DNA (plus 1.6 kb of 5' transcribed sequences), both in tissues of ectodermal and mesodermal origin. The posterior border, however, is not respected, and lacZ expression continues into the tail region. One line has particularly strong graded expression in the anterior proximal limb bud. Other lines, containing a shorter promoter fragment (0.6 kb), have ectopic expression in the head region, including one line that has expression in the anterior half of the retina. Such mouse lines make it possible to molecularly distinguish cells in regions of the embryo that look otherwise identical and may be useful in studying the establishment of molecular differences in the mouse embryo.
A simple method for indirectly verifying noncoplanar treatment fields in radiotherapy.
The use of a vertex field can be a practical technique for treatment of pituitary and brain tumors. This approach may be underutilized, primarily because of the difficulty in documenting noncoplanar treatment fields. This paper describes a method for documenting vertex treatment fields by inference using portal films. This method is relatively simple to implement, yet yields accurate results.
Susceptibility and behavioral response of red imported fire ant (Hymenoptera: Formicidae) to selected entomogenous nematodes (Rhabditida: Steinernematidae & Heterorhabditidae).
Pathogenicity of infective juveniles of selected Steinernema spp. and Heterorhabditis spp. toward developing and reproductive stages of the red imported fire ant, Solenopsis invicta Buren, was tested under laboratory conditions. At 10(3)-10(5) infective juveniles per Petri dish, mortality of reproductive larvae, pupae, and alates ranged from 28 to 100% at higher doses after 96 h at 23-25 degrees C. Steinernema carpocapsae All was the most consistent species tested; this nematode caused mortality of fire ant larvae, pupae, and alates of 82-94, 64-96, and 38-99%, respectively. Although not susceptible to nematode infection, worker ants vigorously preened nematodes from brood, alates, and themselves. In a field study, S. carpocapsae (5 x 10(6) and 2 x 10(6) drench, 2 x 10(6) infective juvenile infection) was applied to active fire ant mounds in 3.8-liter suspensions. Hydramethylnon (75 ml), a water drench, a water injection, and untreated fire ant mounds were marked and treated. Overall activity in mounds treated with nematodes of hydramethylnon ranged from 40 to 48%. Satellite mound activity accounted for 32-44% of overall activity in mounds treated with nematodes 2 wk after treatment. However, 6 wk after treatment, activity in mounds treated with hydramethylnon was 44%; activity of mounds treated with nematodes ranged from 52 to 80%. Satellite mound activity accounted for 0-24% of overall activity. Whereas a soil drench of S. carpocapsae showed potential as a control method for the red imported fire ant, colony relocation after nematode treatment could limit overall efficacy unless application techniques are developed to overcome or take advantage of the movement.