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Biomedical subjects

D A Nelson

Publications and source records attributed to D A Nelson.

At least 19 recordsLinked to original sources
PubMed1997

High molecular weight protein phosphatase type 1 dephosphorylates the retinoblastoma protein.

pRb controls cell proliferation by restricting inappropriate entry of cells into the cell division cycle. As dephosphorylation of pRb during mitotic exit activates its growth suppressive function, identification of the protein phosphatase that dephosphorylates pRb, and characterization of the mechanism of its regulation, are essential to elucidating the mechanisms of cell growth control. By fractionating mitotic CV-1P cell extracts, we identify the protein phosphatase which dephosphorylates pRb as a type 1 serine/threonine phosphoprotein phosphatase (PP1). Molecular sizing analyses indicate that the catalytic enzyme (PP1c) is present in a high molecular weight complex, with a predicted molecular mass of 166 kDa. PP1-interacting proteins in the mitotic cell extracts are identified. Two PP1-interacting proteins (41 and 110 kDa) are shown to form distinct complexes with PP1c from fractions of separated mitotic cell extracts containing phosphorylase phosphatase activity. However, only the 110-kDa PP1-interacting protein is present in fractions containing pRb-directed phosphatase activity, identifying this protein as a putative activator of PP1 function toward pRb during mitosis.

Animals↗
PubMed1997

Ethnic differences in the prevalence of asthma in middle class children.

BACKGROUND: Studies have shown a higher prevalence of asthma among boys compared with girls and in blacks compared with whites, but it has been difficult to separate socioeconomic from racial effects because the blacks in the studied populations were more likely to have low socioeconomic status. OBJECTIVE: To compare the prevalence of asthma in a socioeconomically homogeneous, middle class, multiethnic population of schoolchildren. METHODS: Based on a telephone survey of all families of third-graders in Southfield, Michigan, we ascertained the prevalence of physician-diagnosed asthma and probable undiagnosed asthma. One reason Southfield was chosen for study was because the city comprises an integrated middle class population with only 4% blacks and 7% whites having incomes below federal poverty limits. RESULTS: The lifetime prevalence of asthma was 9.5% (12% for blacks and 6% for whites) and higher in boys (14%) than girls (5%), a pattern that was reflected in period prevalence estimates. The lifetime prevalence of probable undiagnosed asthma was greater in blacks (16.6%) than whites (10.8%), with little sex difference. Adjusting for sex and maternal education, the prevalence of physician-diagnosed asthma and probable asthma were associated independently with black ethnicity. CONCLUSIONS: Our study is unique in the similarity of the black and white families' socioeconomic status and residence in the same middle class community. Since access to medical care and macro-environmental conditions were similar across this study population, our results are consistent with the hypothesis that differences in biologic factors between blacks and whites and boys and girls play a role in asthma risk.

Adolescent↗
PubMed1997

The accumulation of whole body skeletal mass in third- and fourth-grade children: effects of age, gender, ethnicity, and body composition.

The purpose of this longitudinal study is to describe bone mass and body composition, and the annual changes in these measurements, among third grade students recruited from a suburban school district. Whole body bone mineral content (WBBMC), bone mineral density (WBBMD), fat, and lean mass were measured by dual-energy X-ray absorptiometry. Bone mass in the lumbar spine (LBMC) region of the whole body scan was also utilized. 773 students (38% white, 57% black, 5% other) had baseline visits; 561 had a second measurement a year later. At baseline, black children have significantly higher WBBMC, WBBMD, height, and lean mass than whites. Black males, but not black females, have a greater LBMC. There are no significant gender differences in body size, WBBMC, or WBBMD, although girls have a greater LBMC and fat mass, and boys have a higher lean mass. Most of these differences persist in visit 2. The annual change in bone and lean mass is greater in blacks. Stepwise linear regression analyses of bone mass on body size, gender, and ethnicity and their interactions indicate that log-transformed weight explains most of the variance in both WBBMC and WBBMD (multiple r2 = 0.90 and 0.64, respectively). There are significant black/white differences in intercepts and slopes. Other variables explain only another 1%-2% of the variance. The strongest Pearson correlations are between changes in bone mass and changes in lean mass and log-transformed weight (r ranging from 0.62 to 0.84, p = 0.0001). We conclude that there is a significant black/white, but not male/female difference in whole body bone mass and bone density before puberty. Ethnic and gender differences in bone and body composition suggest that the lean component may contribute to a greater peak bone mass in blacks vs. whites, and perhaps in males vs. females.

Absorptiometry, Photon↗
PubMed1996

The high-affinity sulfonylurea receptor: distribution, glycosylation, purification, and immunoprecipitation of two forms from endocrine and neuroendocrine cell lines.

The high-affinity sulfonylurea receptor, a novel member of the ATP-binding cassette superfamily, is one component of the ATP-sensitive K+ channel. The protein is critical for regulation of insulin secretion from pancreatic beta-cells, and mutations in the receptor have been linked to familial hyperinsulinemia, a disorder characterized by unregulated insulin release despite severe hypoglycemia. The sulfonylurea receptor is present in membranes from a number of endocrine and neuroendocrine cell lines, including HIT-T15, RINm5f, alpha TC-6, AtT-20, and GH3 cells. Two forms of the receptor are present in RINm5f and alpha TC-6 cells, with apparent SDS gel molecular masses of 140 and 150 kDa. The two forms have equally high affinity, KD approximately 3 nM, for an iodinated derivative of glyburide, an anti-diabetic sulfonylurea. The receptor is a glycoprotein; treatment of RINm5f or alpha TC-6 cells with tunicamycin reduces the 140 and 150 kDa species to a single approximately 137 kDa protein. The 140 and 150 kDa receptors bind differentially to concanavalin A and wheat germ agglutinin, and lectin-affinity chromatography is ideal for the initial stages of receptor purification. After lectin-affinity chromatography, the same methods can be applied for purifying the 150 kDa form as for the 140 kDa receptor. A transiently expressed receptor with a histidine-tagged carboxy-terminus was purified by Ni-agarose chromatography, and this variant was used to demonstrate that the 140 kDa polypeptide is full length. Anti-peptide antibodies directed against the amino-terminus of the receptor and antibodies against the nucleotide binding folds immunoprecipitate both receptor forms. The results indicate the 140 and 150 kDa receptors are differentially glycosylated forms of the same polypeptide chain.

ATP-Binding Cassette Transporters↗
PubMed1996

Clinical utility of bone mass measurements in adults: consensus of an international panel. The Society for Clinical Densitometry.

Low bone mass predicts future fracture risk as well as high cholesterol or high blood pressure can predict the risk of heart disease or stroke. Prevention of the first fracture should be a clinical goal. In patients without fractures, osteopenia and osteoporosis can be diagnosed based on the extent of reduction in bone mass below mean peak bone mass of young healthy individuals. As bone mass decreases, fracture risk increases exponentially. Clinical situations in which an assessment of bone mass and fracture risk affects therapeutic decisions include estrogen deficiency, vertebral abnormalities, radiographic osteopenia, asymptomatic primary hyperparathyroidism, and long-term corticosteroid therapy. Serial measurements can also be used to monitor the effects of osteoporosis treatments. The appropriate technique and skeletal site for bone mass measurements should be chosen based on the patient's circumstances and the precision of measurement. A clinical interpretation can enhance the value of computer-generated bone mass measurement reports and improve decision making.

Absorptiometry, Photon↗
PubMed1996

Slopes of distortion-product otoacoustic emission growth curves corrected for noise-floor levels.

Distortion-product otoacoustic emission (DPE) input/output (I/O) curves were measured at 2f1-f2 frequencies with spectral-averaging and time-averaging procedures from ten normal-hearing ears. Stimuli were equal-level f1 and f2 primary tones with f2/f1 ratios of 1.2 and f2 frequencies at 1200, 2400, and 4800 Hz. Time-averaging procedures lowered noise-floor (NF) levels, compared to spectral averaging, so DPEs could be elicited by stimuli as low as 18 dB SPL in some ears. DPEs were corrected for power summation with NF levels and the resulting DPE I/O curves were fit with sixth-order polynomials. Slopes of fitted I/O curves were specified by the first derivative as a function of the level of the primary tones. Slopes of uncorrected spectrally averaged DPE I/O curves were strongly influenced by the NF level. Slopes of NF-corrected spectrally averaged DPE I/O curves were more representative of the true slope, specified as the slope of the corresponding time-averaged DPE I/O curve well above its NF. True DPE I/O slopes decreased with level from a mean slope near 1.0 dB/dB at 30 dB SPL and below for all three f2 frequencies. Nonmonotonicities in I/O curves were not seen at very low stimulus levels. At moderate stimulus levels and above, nonmonotonicities in individual DPE I/O curves reduced the slopes of individual I/O curves and reduced the average slopea cross ears.

Acoustic Stimulation↗
PubMed1996

Release from upward spread of masking in regions of high-frequency hearing loss.

The upward spread of masking was compared for 500-Hz quasifrequency-modulated (QFM) and sinusoidally amplitude-modulated (SAM) maskers. The modulation rate was 20 Hz. These maskers had identical magnitude spectra but different envelopes, which were relatively flat for the QFM masker and strongly fluctuating for the SAM masker. At signal frequencies more than an octave above the masker, masked thresholds for the SAM masker were lower than for the QFM masker, revealing "masking release" (QFM-SAM masked threshold differences) exceeding 30 dB in normal-hearing ears. In ears with high-frequency sensorineural hearing loss, but normal hearing in the region of the masker, masking release was markedly reduced or completely absent in regions of hearing loss. The data were evaluated with a model of masking based on the linearized response growth (LRG) of basilar membrane transfer functions associated with cochlear damage in animals. The LRG model predicted more gradual slopes of the growth of masking and reduced amount of masking in regions of hearing loss. The reduced masking release seen in regions of hearing loss could be largely accounted for by a more rapid growth of response to the probe tone in regions of hearing loss.

Auditory Perception↗
PubMed1996

Intensity discrimination as a function of stimulus level with electric stimulation.

Difference limens (DLs) for changes in electric current were measured from multiple electrodes in each of eight cochlear-implanted subjects. Stimuli were 200-microseconds/phase biphasic pulse trains delivered at 125 Hz in 300-ms bursts. DLs were measured with an adaptive three-alternative forced-choice procedure. Fixed-level psychometric functions were also obtained in four subjects to validate the adaptive DLs. Relative intensity DLs, specified as Weber fractions in decibels [10 log (delta I/I)] for standards above absolute threshold, decreased as a power function of stimulus intensity relative to absolute threshold [delta I/I = beta (I/I0) alpha] in the same manner as Weber fractions for normal acoustic stimulation reported in previous studies. Exponents (alpha) of the power function for electric stimulation ranged from -0.4 to -3.2, on average, an order of magnitude larger than exponents for acoustic stimulation, which range from -0.07 to -0.11. Normalization of stimulus intensity to the dynamic range of hearing resulted in Weber functions with similar negative slopes for electric and acoustic stimulation, corresponding to an 8-dB average improvement in Weber fractions across the dynamic range. Sensitivity to intensity change ¿10 log beta¿ varied from -0.42 to -13.5 dB compared to +0.60 to -3.34 dB for acoustic stimulation, but on average was better with electric stimulation than with acoustic stimulation. Psychometric functions for intensity discrimination yielded Weber fractions consistent with adaptive procedures and d' was a linear function of delta I. Variability among repeated Weber-fraction estimates was constant across dynamic range. Relatively constant Weber fractions across all or part of the dynamic range, observed in some subjects, were traced to the intensity resolution limits of individual implanted receiver/stimulators. DLs could not be accurately described by constant amplitude changes, expressed as a percentage of dynamic range ¿delta A(% DR)¿. Weber fractions from prelingually deafened subjects were no better or worse than those from postlingually deafened subjects. The cumulative number of discriminable intensity steps across the dynamic range of electric hearing ranged from as few as 6.6 to as many as 45.2. Physiologic factors that may determine important features of electric intensity discrimination are discussed in the context of a simple, qualitative, rate-based model. These factors include the lack of compressive cochlear preprocessing, the relative steepness of neural rate-intensity functions, and individual differences in patterns of neural survival.

Auditory Threshold↗
PubMed1995

Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulin secretion.

Sulfonylureas are a class of drugs widely used to promote insulin secretion in the treatment of non-insulin-dependent diabetes mellitus. These drugs interact with the sulfonylurea receptor of pancreatic beta cells and inhibit the conductance of adenosine triphosphate (ATP)-dependent potassium (KATP) channels. Cloning of complementary DNAs for the high-affinity sulfonylurea receptor indicates that it is a member of the ATP-binding cassette or traffic ATPase superfamily with multiple membrane-spanning domains and two nucleotide binding folds. The results suggest that the sulfonylurea receptor may sense changes in ATP and ADP concentration, affect KATP channel activity, and thereby modulate insulin release.

ATP-Binding Cassette Transporters↗
PubMed1995

Morphologic characteristics of erythroleukemia (acute myeloid leukemia; FAB-M6): a CALGB study.

We have reviewed the clinical, morphologic, immunophenotypic, and cytogenetic features of 52 patients with erythroleukemia (FAB Cooperative Group; AML-M6) studied by the Cancer and Leukemia Group B (CALGB). The purpose of this study was to correlate morphology with the clinical features, immunophenotypes, and karyotypes of neoplastic cells, and with the response to therapy of patients with AML-M6. Thirty-three patients (63%) were male, median age 59 (range 16-81) years, 47 patients (90%) were white, and 42 patients (81%) had a performance status of < 2. Myelodysplastic changes were observed in at least 1 cell lineage in all cases, and in 2 cell lineages in 45 of 52 (86%) cases. Fifty percent or more of cases studied were positive for CD11b, CD13, CD15, CD33, glycophorin-A, and HLA-DR markers. Fourteen of 27 cases (52%) in whom karyotypic analyses were conducted had cytogenetic abnormalities. Five (19%) were simple (< 3 karyotypic abnormalities), while 9 (33%) were complex (> or = 3 abnormalities). We observed either a complete or partial loss of chromosomes 5, 7, or 12p, or the presence of trisomy 8, in 11 of 27 (41%) patients. Cases of AML-M6 were divided into group 1 (14 patients with bone marrow proerythroblasts and basophilic erythroblasts > 25% of all erythroblasts) and group 2 (38 patients with proerythroblasts and basophilic erythroblasts < or = 25% of all erythroblasts). We observed no significant differences between groups 1 and 2 in regard to sex, age, race, performance status, percentage of blood erythroblasts or myeloblasts, percentage of bone marrow erythroblasts, and periodic acid-Schiff (PAS) or myelodysplasia scores. Six of 6 (100%) patients of group 1, and 7 of 21 (33%) patients of group 2, had normal karyotypes (P = .006). Nine of 13 (69%) patients of group 1 and 15 of 33 (45%) patients of group 2 had a complete remission (CR) (P = .2). Eight of 11 (73%) cytogenetically normal patients achieved CR: 5 of 6 (83%) in group 1, and 3 of 5 (60%) in group 2. Five of 12 (42%) cytogenetically abnormal patients achieved CR. No difference in duration of survival (group 1, median = 4.6 months vs. group 2, median = 10.2 months; P = .93) was observed between the 2 groups. We conclude that AML-M6 is typified by multilineage involvement of hematopoietic cells. The morphology of erythroblasts in patients with AML-M6 may correlate with cytogenetic abnormalities and rate of CR.

Adolescent↗
PubMed1995

Testosterone-induced shortening of the storage phase of song development in birds interferes with vocal learning.

Bird song is a complex, learned behavior. Vocal learning in sparrows involves several different processes that occur in a distinct temporal pattern over the course of the first year of life. Songs are acquired without practice during a sensitive period within the first 3 months of life and rehearsal of the acquired song does not begin until 7 or 8 months of age. The function of the storage period between song acquisition and production is not known. We set out to investigate its significance by administering testosterone, known to stimulate production of adult song, to birds at 100 days of age after song acquisition was completed but some 5 months prior to normal song onset. Most testosterone-treated birds produced abnormal songs resembling those of males raised in acoustic isolation suggesting that, in sparrows, events occurring during the storage phase play a significant role in vocal learning.

Animals↗
PubMed1995

Ethnic differences in regional bone density, hip axis length, and lifestyle variables among healthy black and white men.

There are few published data on bone mass, measured by dual-energy X-ray absorptiometry (DXA), in healthy white or black men. Similarly, a recently described predictor of hip fracture among white women, hip axis length (HAL), has not been studied in men. We recruited 160 white and 34 black men, aged 23-80 years, and screened for diseases and drug exposures that adversely affect skeletal health. We measured bone mineral density (BMD) in the lumbar spine, femoral neck, and radial shaft by DXA; height and weight; skin color by reflectometry; and hip axis length both directly from DXA output and using automated software in a subsample. We also obtained historical data on education, smoking, exercise, and fractures. There were no significant black/white differences in mean weight, height, body mass index (BMI), or HAL. The black men had higher BMDs than did the white men at every site (5% for the radius, 10% for the lumbar spine, and 20% for the femoral neck). Skin pigmentation and BMD were not significantly correlated in either group (p > 0.38). Among the white men, smoking was associated with lower lumbar BMD, but there was no significant relationship between BMD and exercise frequency in either group. There was no significant ethnic difference in fracture experience. We conclude that: (1) the higher BMD in black men than in white men is not due to greater body size, (2) the lower hip fracture risk reported for black men than for white men is not due to a difference in hip axis length; (3) skin color is not related to BMD in either sex.

Absorptiometry, Photon↗
PubMed1995

Effect of the kinase inhibitor 2-aminopurine on the cell cycle stage-dependent phosphorylation state of the retinoblastoma protein.

We investigated the effect of 2-aminopurine (2-AP) on the cell cycle stage-dependent phosphorylation state of the retinoblastoma growth suppressor protein (pRB). Our results suggest that 2-AP does not affect dephosphorylation of pRB scheduled during metaphase/anaphase of mitosis, even though 2-AP-treated cells never enter metaphase or anaphase. Phosphorylation of pRB, which is important for G1 exit, appeared to be impeded by 2-AP late during G1, coincident with a slowing of G1 cell progression into S phase. The significance of these data with regard to cell cycle regulation is discussed.

2-Aminopurine↗
PubMed1995

Control and activity of type-1 serine/threonine protein phosphatase during the cell cycle.

The first part of this discourse will serve as a compendium of selected aspects of PP1 activity and control during the cell cycle. The latter sections will focus on the mammalian cell cycle dependent activity of PP1 on the negative growth regulatory product of the retinoblastoma susceptibility gene, pRB. The purpose here is to suggest one possible mechanism to explain how this phosphatase can effect cell cycle progression. An argument is made for PP1 playing an indirect role in regulating cell cycle progression by modulating the growth suppressive activity of pRB.

Animals↗
PubMed1995

Influence of temperature changes on multiple sclerosis: critical review of mechanisms and research potential.

In 1890, Uhthoff studied multiple sclerosis (MS) patients who developed amblyopia following exercise, a phenomenon later discovered to be secondary to elevated body temperature from muscular activity. Six decades later, the hot bath test and various other heating reactions (HR) began to be used diagnostically. They were essentially discontinued after 1983, being replaced by more specific and safer tests and procedures. Over 80% of MS patients develop a panoply of neurological signs during hyperthermia, 60% of which are "new" to that patient. The literature contains a number of unexplained paradoxical responses of MS patients during induced hyperthermia. These challenge the current hypothesis that, in MS, hyperthermia induces a heat-linked neuro-blockade of partially demyelinated axons. Some MS patients developed signs before temperature elevations occurred; others showed clearing of signs while temperatures were elevated or were ascending. Several MS patients improved for about 3 hours after being tested, a rebound phenomenon known as "overshoot." Conversely, other MS patients developed persistent neurological deficits after hyperthermia. The etiology of HR may be multifactorial. This includes heat itself, effects of serum calcium, blockade of ion channels, circulatory changes, heat shock proteins, and unidentified humoral substances. Research techniques are suggested to continue investigations into the enigma of HR, hopefully to widen knowledge of demyelination.

Amblyopia↗