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Biomedical subjects

D A Nelson

Publications and source records attributed to D A Nelson.

At least 109 records · Page 6Linked to original sources
PubMed1992

Anti-immunoglobulin treatment of murine B-cell lymphomas induces active transforming growth factor beta but pRB hypophosphorylation is transforming growth factor beta independent.

Cross-linking of B-cell membrane immunoglobulin (Ig) receptors induces growth arrest at G1-S, leading to apoptosis and cell death in the immature lymphomas WEHI-231 and CH31, but not in the CH12 B-cell line. In this system, which has been used as a model for B-cell tolerance, we have established that these lymphomas produce active transforming growth factor beta (TGF-beta) when treated with anti-Ig and that their hierarchy of sensitivity to TGF-beta generally correlates with their growth inhibition by anti-Ig. TGF-beta, in turn, has been shown to interfere with the phosphorylation of the retinoblastoma gene product, pRB. Herein, we also demonstrate that in WEHI-231 B-lymphoma cells treated with anti-Ig for 24 h, the pRB protein is found to be predominantly in the underphosphorylated form, as previously reported for cells arrested by the exogenous addition of TGF-beta. However, neutralizing antibodies to TGF-beta failed to prevent growth inhibition by anti-Ig in WEHI-231 and CH31. When WEHI-231 lymphoma cells were selected for growth in TGF-beta, the majority of the TGF-beta-resistant clones remained sensitive to anti-Ig-mediated growth inhibition. In these clones, the retinoblastoma gene product was found to be in the underphosphorylated form after 24-h treatment with anti-Ig, but not with TGF-beta. These data show that anti-Ig treatment of murine B-cell lymphomas stimulates the production of active TGF-beta but that a TGF-beta-independent pathway may be responsible for the pRB underphosphorylation and cell cycle blockade.

Animals↗
PubMed1991

Principal components analysis of regional bone density in black and white women: relationship to body size and composition.

Black and white women in the United States differ with respect to bone mass and the risk of developing osteoporosis. It has been suggested that greater body size among U.S. blacks may contribute to greater bone density in this group. It is not known whether the fat or lean component contributes more to this relationship. Bone density was measured at seven sites in 161 normal black and white women using single and dual photon absorptiometry. The first principal component accounted for 73% of the variance in the sample and constitutes an index of skeletal mass. The second principal component added another 10% and contrasts the axial and appendicular sites. Both the regional bone densities and the first principal component showed significantly greater bone densities for blacks; adjustment for body size reduced bone mass differences by approximately 50%. Body composition analysis done on a subset of these women indicated that the fat component of body mass may be the more important factor in its effect on bone mass.

Absorptiometry, Photon↗
PubMed1991

Comparison of dual photon and dual energy X-ray bone densitometers in a clinic setting.

In clinical practice, decisions must be made about whether and how to convert to newer technologies. To address this issue, two separate studies were conducted. We evaluated the relationships between results of lumbar spine measurements using two dual photon absorptiometry (DPA1 and DPA2) instruments and one dual energy X-ray (DXA) instrument with the same subjects (49 volunteers), and also in 65 patients who were measured on the DPA1 and DXA machines. Second, we measured the lumbar spine and the proximal femur in three groups of 12 female volunteers three times on one instrument within 1 week. We purposely simulated a busy clinic setting with different technologists, older radioactive sources, and a heterogeneous patient group. The comparison study indicated a significant difference between the mean bone density values reported by the machines, but the results were highly correlated (R2 = 0.89-0.96). The short-term precision errors (coefficients of variation) differed among the instruments, ranging from 1.3% (DXA of the spine) to 5.1% (DPA1 of the spine), and in the femoral neck, 2.3% and 2.4% (DXA and DPA1, respectively) versus 3.5% by DPA2. This study emphasizes the differences between instruments, the potential for greater error in busy clinic environments, and the apparent superiority of dual energy X-ray absorptiometry under these less than ideal conditions.

Absorptiometry, Photon↗
PubMed1991

A randomized trial of sodium fluoride as a treatment for postmenopausal osteoporosis.

The anti-fracture efficacy of sodium fluoride (NaF) was evaluated in 84 postmenopausal white women with spinal osteoporosis. The dose of NaF used was 75 mg/day and all patients in this prospective, randomized, double-blind, placebo-controlled clinical trial received calcium supplements (carbonate salt) 1500 mg/day in addition to participating in a structured physical therapy program. For each of the outcome measures (change in stature, change in cortical bone mass in the forearm and development of new vertebral fractures determined by change in vertebral morphometry and by scintigraphy) there was no significant difference between the fluoride or placebo treated groups. Side effects, predominantly gastrointestinal symptoms and the development of the painful lower extremity syndrome, occurred significantly more frequently in the fluoride group (P less than 0.05). Peripheral fractures were not more frequent in the fluoride group. We conclude that, in the dose and manner used in this study, NaF is no more effective than placebo in retarding the progression of spinal osteoporosis. There is no role for NaF in the treatment of osteoporosis outside the confines of clinical research.

Aged↗
PubMed1991

Sulfonylurea signal transduction.

In the pancreatic beta cells the proximal step in sulfonylurea signal transduction is the binding of these clinically important drugs to high-affinity receptors in the beta cell membrane. Using HIT cells as a model system, we have established an extremely close correlation between the affinity of binding of glyburide and its analog, iodoglyburide, and the activation of various steps in stimulus-secretion coupling--inhibition of 86Rb+ efflux, increase in [Ca2+]i resulting from gating of voltage-gated calcium channels by cell depolarization, and the exocytosis of insulin. Two different L-type channel cDNAs have been identified in an HIT cell library, one neuroendocrine in type and one more cardiac-like. A HIT cell membrane protein of Mr 140,000, which we believe to be the high-affinity sulfonylurea receptor, can be covalently linked to 5(125)-iodo-2-hydroxyglyburide by ultraviolet irradiation. The receptor has been solubilized and retains binding activity and the same rank order of displacement of the 5(125)-iodo-2-hydroxyglyburide as observed with the native receptor. The Mr 140,000 protein has been partially purified and the amino acid sequences of three proteolytic fragments have been used to design oligonucleotides to screen HIT cell cDNA libraries. Since the binding constant of glyburide or iodoglyburide is closely correlated with the ability of these compounds to inhibit the ATP-sensitive K+ channel, increase [Ca2+]i, and elicit insulin secretion, we have identified the Mr 140,000 protein as the sulfonylurea receptor. Expression of the cloned cDNA should allow us to test this hypothesis directly.

ATP-Binding Cassette Transporters↗
PubMed1991

High-level psychophysical tuning curves: simultaneous masking with different noise bandwidths.

Simultaneous-masked psychophysical tuning curves were measured with narrow-band noise maskers varying in bandwidth from 40 Hz to 800 Hz to determine the masker bandwidths at which combination-band detection cues no longer influence tuning-curve shapes. Tuning curves were obtained at 1000 and 4000 Hz from normal-hearing listeners using high-level (60 dB SPL) probe tones in quiet and in the presence of a broadband background noise to eliminate combination bands and other off-frequency listening cues that exist at high levels. High-level tuning curves revealed notches on the low-frequency sides. Those notches were eliminated with broad-band background noise, which indicates that combination bands can strongly influence the shapes of high-level tuning curves obtained with narrow-band maskers, primarily by steepening the low-frequency and tail slopes. Combination-band detection cues had a stronger influence at 4000 Hz than at 1000 Hz. As masker bandwidth increased, combination bands had less influence on tuning-curve shapes. These results suggest a possible relation between masker bandwidth and auditory critical bandwidth: combination bands affected the low-frequency sides of the tuning curves only when the masker bandwidth was less than the auditory critical bandwidth.

Acoustics↗
PubMed1991

Frequency discrimination as a function of signal frequency and level in normal-hearing and hearing-impaired listeners.

Frequency difference limens (DLFs) for pure tones were obtained over a wide range of frequencies and levels from 7 normal-hearing subjects and 16 ears of 12 listeners with sensorineural hearing losses. The normal data were fitted with a general prediction equation. Variability of the data around the DLFs estimated by the equation was quantified and used to evaluate the DLFs from the hearing-impaired listeners. The majority of DLFs from impaired listeners were poorer than one standard deviation above the estimates of the normal equation at all frequencies and sensation levels (SLs). The portion of the equation concerned with sensation level was fitted to each listener's data at each frequency. The slopes of these functions indicated that, on average, the rate of improvement of the DLF with sensation level was similar in the two groups of subjects. These results suggest that it would be reasonable to compare DLFs from normal-hearing and hearing-impaired listeners at equivalent sensation levels. The intercepts of the DLF-intensity functions represent asymptotic values obtained at high SLs. These asymptotic DLFs were abnormal in the majority of hearing-impaired subjects, with more than half the data in excess of two standard deviations above normal. However, among those subjects, the correlation between the DLF deficit and the amount of hearing loss at the test frequency was not strong (r = +.27).

Acoustics↗
PubMed1991

Calcium in evolutionary perspective.

The nutritional requirements of contemporary humans were almost certainly established over eons of evolutionary experience and the best available evidence indicates that this evolution occurred in a high-calcium nutritional environment. The exercise and dietary patterns of humans living at the end of the Stone Age can be considered natural paradigms: calcium intake was twice that for contemporary humans and requirements for physical exertion were also greater than at present. Bony remains from that period suggest that Stone Agers developed a greater peak bone mass and experienced less age-related bone loss than do humans in the 20th Century.

Agriculture↗
PubMed1991

High-level psychophysical tuning curves: forward masking in normal-hearing and hearing-impaired listeners.

Forward-masked psychophysical tuning curves (PTCs) were obtained for 1000-Hz probe tones at multiple probe levels from one ear of 26 normal-hearing listeners and from 24 ears of 21 hearing-impaired listeners with cochlear hearing loss. Comparisons between normal-hearing and hearing-impaired PTCs were made at equivalent masker levels near the tips of PTCs. Comparisons were also made of PTC characteristics obtained by fitting each PTC with three straight-line segments using least-squares fitting procedures. Abnormal frequency resolution was revealed only as abnormal downward spread of masking. The low-frequency slopes of PTCs from hearing-impaired listeners were not different from those of normal-hearing listeners. That is, hearing-impaired listeners did not demonstrate abnormal upward spread of masking when equivalent masker levels were compared. Ten hearing-impaired ears demonstrated abnormally broad PTCs, due exclusively to reduced high-frequency slopes in their PTCs. This abnormal downward spread of masking was observed only in listeners with hearing losses greater than 40 dB HL. From these results, it would appear that some, but not all, cochlear hearing losses greater than 40 dB HL influence the sharp tuning capabilities usually associated with outer hair cell function.

Acoustics↗
PubMed1991

High-level psychophysical tuning curves: simultaneous masking by pure tones and 100-Hz-wide noise bands.

Simultaneous-masked psychophysical tuning curves were obtained from normal-hearing listeners using low-level (20-25 dB SPL) probe tones in quiet and high-level (60 dB SPL) probe tones, both in quiet and in the presence of a broad-band background noise. The background noise was introduced to eliminate combination tones or combination bands and other off-frequency listening cues that exist at high levels. Tuning curves were obtained using pure-tone maskers and 100-Hz-wide narrow-band noise maskers for probe tones at 1000 and 4000 Hz. High-level tuning curves for pure-tone maskers demonstrated large discontinuities or "notches" on the low-frequency sides of the tuning curves. Broad-band background noise eliminated those notches, indicating that the notches were due to the detection of off-frequency listening cues at combination-tone frequencies. High-level tuning curves for 100-Hz-wide narrow-band maskers also demonstrated notches on the low-frequency sides. Those notches were eliminated with broad-band background noise, which indicates that combination bands strongly influenced the shapes of high-level tuning curves obtained with narrow-band maskers. The influence of combination bands was dependent upon test frequency. At 1000 Hz, combination bands had very little influence on the shapes of high-level tuning curves. At 4000 Hz, where the masker bandwidth was substantially less than the critical bandwidth, combination bands strongly affected the low-frequency sides of the tuning curves. In 2 subjects tested at a probe frequency of 2000 Hz with 100-Hz-wide masking bands, combination bands also influenced the low-frequency sides of high-level tuning curves. The presence of combination-tone or combination-band cues essentially steepened the low-frequency slopes of tuning curves, resulting in sharper estimates of tuning. Comparisons of tuning curves obtained with pure-tone maskers and narrow-band maskers, in the same listeners, revealed that pure-tone maskers were more effective than narrow-band maskers when the masker frequencies were in the tail region of the tuning curve. The results of these experiments support the notion that tuning in the normal auditory system broadens notably with stimulus level, once off-frequency listening cues such as combination tones or combination bands are eliminated. The low-level simultaneously masked tuning curve demonstrates a sharp bandpass tuning characteristic, whereas the high-level simultaneously masked tuning curve in background noise demonstrates a broad low-pass tuning characteristic.(ABSTRACT TRUNCATED AT 400 WORDS)

Acoustics↗
PubMed1991

Numerical simulation of heating from an acrylic implant in bone.

Heat transfer in an acrylic cement-bone system during hyperthermia has been has been simulated by using a spectral element method, using a 2-D linear model which combines the geometric flexibility of low-order finite element methods and high accuracy of spectral methods. The work is directed at obtaining a fundamental understanding of factors affecting hyperthermia therapy applied to giant cell tumors of bone in a two-dimensional model at a cross-section of the distal femur. Results suggest the heating may be significant within approximately 4 mm to 7 mm of the interface of the acrylic and the cancellous bone. Computational results are compared with published experimental results.

Bone Cements↗
PubMed1990

Molecular mechanisms of action of glyburide on the beta cell.

A high-affinity sulfonylurea receptor has been identified on the plasma membrane of the beta cell. The potent second-generation sulfonylureas, glyburide and glipizide, saturate the receptor in the low nM concentration range, whereas first-generation drugs bind to and saturate the receptor in the microM range. For each of the sulfonylureas, there is excellent quantitative agreement among the equilibrium binding constant (Kd), the half-maximal inhibition of potassium ion (K+) efflux (K0.5), and the half-maximal stimulation of insulin secretion (ED50), when these values are obtained from insulin-secreting cell lines or from isolated mouse pancreatic islets. The inhibition of K+ efflux by the sulfonylureas, coupled with the sulfonylurea inhibition of the activity of a specific adenosine triphosphate (ATP)-sensitive K+ channel embedded in the plasma membrane of whole cells or in excised membrane patches, suggests that the sulfonylurea receptor is this channel protein or a closely associated subunit. The activity of the ATP-sensitive K+ channel is also controlled by the insulin secretagogues, glucose and certain amino acids. These compounds must be metabolized to inhibit the channel activity and appear to do so by increasing the level of ATP or by increasing the ATP/adenosine diphosphate (ADP) ratio. ATP reduces channel activity by binding to a specific nucleotide-binding site on the cytoplasmic surface of the protein. There is a synergy between the action of glucose and that of the sulfonylureas. The sulfonylureas, for example, are better effectors of insulin secretion in the presence of glucose. Inhibition of the ATP-sensitive K+ channels results in depolarization of the plasma membrane and a subsequent influx of extracellular calcium ions through voltage-dependent calcium channels. An increase in the free intracellular calcium level is the signal, or "second messenger," that triggers exocytosis and the release of insulin. The sulfonylurea receptor has a molecular weight of 140,000 and can be solubilized by digitonin, retaining the same rank order of sulfonylurea binding affinities as the membrane-bound protein. Several laboratories are currently purifying the receptor and/or cloning the receptor gene.

Adenosine Triphosphate↗
PubMed1990

Photoaffinity labeling and partial purification of the beta cell sulfonylurea receptor using a novel, biologically active glyburide analog.

An iodinated analog of the sulfonylurea, glyburide, has been synthesized which can be labeled to high specific activity and used to photolabel the sulfonylurea receptor. 5-Iodo-2-hydroxy-"glyburide", has an iodo group replacing the chlorine at position 5 and a methoxy residue replacing the hydroxy group at position 2 on the benzamido ring. This analog retains biologic activity stimulating insulin secretion from a hamster beta cell line (HIT cells) at the same ED50 (0.4 nM) as glyburide. Scatchard analysis demonstrated high and low affinity binding sites on HIT cell membranes (Kd values of 0.36 nM and 277 nM and Bmax values of 1.6 and 100 pmol/mg of membrane protein, respectively). Competitive binding assays with unlabeled glyburide or 5-iodo-2-hydroxyglyburide yield Ki values of 0.5 and 1.0 nM, respectively. The analog can be covalently linked by ultraviolet irradiation to a membrane protein of Mr = 140,000. The photolabeling is completely blocked by unlabeled glyburide or the analog. Two other species of Mr = 65,000 and 43,000 are also photolabeled; these may be the low affinity sites. After photolabeling, the receptor has been purified partially by chromatographic procedures and is suitable for obtaining peptide sequence. The 140,000 molecular weight protein is identified as the sulfonylurea receptor since its binding constant, 0.36 nM, is closely correlated with its ability to stimulate insulin secretion (ED50 congruent to 0.4 nM).

ATP-Binding Cassette Transporters↗
PubMed1990

Effects of stimulus level on forward-masked psychophysical tuning curves in quiet and in noise.

Forward-masked psychophysical tuning curves were obtained from normal-hearing listeners at different probe levels in quiet and in a broadband background noise. In quiet, tuning-curve shape changed with probe level. For six listeners, tuning curves became broader with increasing probe level, primarily due to a decrease in the low-frequency slopes. For one listener, tuning curves became narrower with increasing probe level. The addition of a background noise, which was presented continuously at a level 10 dB below the noise level required to mask the probe tone, reduced the masker levels required to mask the probe tone. The reduction was greater near the tip of the tuning curve than on the tail, so that tuning curves in background noise were narrower than those obtained in quiet. Tuning curves with comparable masker levels near the tip of the tuning curve (Lmtip) were similar in shape, regardless of probe level or whether tuning curves were obtained in quiet or noise. Comparisons of tuning-curve characteristics derived by fitting tuning curves with least-squares procedures, indicated that low-frequency slopes decreased with Lmtip. As a consequence, Q10 dB values decreased with Lmtip. These results are consistent with the interpretation that tuning-curve shapes are determined by the intensities of the maskers required to mask the probe tone. The addition of a background noise restricted (partially masked) the excitation pattern of the probe so that lower masker intensities were required to "forward mask" the probe tone, and narrower tuning curves resulted from less intense markers. The results are well described by a two-process model of auditory excitation patterns.

Adult↗