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Biomedical subjects

G Johnson

Publications and source records attributed to G Johnson.

At least 91 records · Page 5Linked to original sources
PubMed2000

Activation of MEK kinase 1 by the c-Abl protein tyrosine kinase in response to DNA damage.

The c-Abl protein tyrosine kinase is activated by certain DNA-damaging agents and regulates induction of the stress-activated c-Jun N-terminal protein kinase (SAPK). Here we show that nuclear c-Abl associates with MEK kinase 1 (MEKK-1), an upstream effector of the SEK1-->SAPK pathway, in the response of cells to genotoxic stress. The results demonstrate that the nuclear c-Abl binds to MEKK-1 and that c-Abl phosphorylates MEKK-1 in vitro and in vivo. Transient-transfection studies with wild-type and kinase-inactive c-Abl demonstrate c-Abl kinase-dependent activation of MEKK-1. Moreover, c-Abl activates MEKK-1 in vitro and in response to DNA damage. The results also demonstrate that c-Abl induces MEKK-1-mediated phosphorylation and activation of SEK1-SAPK in coupled kinase assays. These findings indicate that c-Abl functions upstream of MEKK-1-dependent activation of SAPK in the response to genotoxic stress.

Animals↗
PubMed2000

Comparison of different methods of obtaining orthostatic vital signs.

The purpose of this study was to compare two lying and standing procedures for measuring orthostatic vital signs. Thirty-five normotensive participants (mean age 21.6 years)participated in a randomized crossover study. Measures of blood pressure (BP), heart rate, and dizziness were collected at different lying and standing times. AU subjects participated in a standardized walk paced at 4 miles per hour prior to lying. Using analysis of variance (ANOVA) with post hoc contrasts, the mean systolic BP differed between 5 and 10 minutes of lying (F = 21.33, p < .001) and the mean diastolic BP tended to differ between those time points (F = 5.23, p < .03). The mean standing systolic BP and dizziness rating were different between 0- and 2-minute intervals (F = 8.36, p < .01 and F = 7.15, p < .10). In normotensive participants following standardized exercise, orthostatic vital signs stabilized after lying 10 minutes.

Adult↗
PubMed2000

New therapeutic strategies for lung cancer: biology and molecular biology come of age.

The current understanding of the biology and molecular biology of lung cancer pathogenesis and progression is reviewed. Awareness of the influence of growth factors, oncogenes, and tumor suppressor genes as well as signal transduction and angiogenesis pathways on the natural history of cancer cells has led to attempts to develop new therapeutic strategies directed at interrupting tumor cell growth. Treatments utilizing monoclonal antibodies, matrix metalloproteinase inhibitors, and gene transfer and alteration are currently being investigated. The rationale and effectiveness of these treatments in early trials are explored, and recommendations for future directions in cell biology research are presented. Interest in the biology and molecular biology of tumor cells has led to some important findings that may provide opportunities for new treatments. Several of these new directions for anticancer therapy are already being examined in phase I clinical trials.

Antineoplastic Agents↗
PubMed2000

Angiotensin-converting enzyme inhibitor-enhanced phase-contrast MR imaging to measure renal artery velocity waveforms in patients with suspected renovascular hypertension.

OBJECTIVE: We investigated the usefulness of phase-contrast MR imaging to measure renal artery velocity waveforms as an adjunct to renal MR angiography. We also examined whether an angiotensin-converting enzyme (ACE) inhibitor improves the diagnostic accuracy of waveform analysis. SUBJECTS AND METHODS: Thirty-five patients referred for MR angiography of renal arteries underwent non-breath-hold oblique sagittal velocity-encoded phase-contrast MR imaging through both renal hila (TR/TE, 24/5; flip angle, 30 degrees; signal averages, two; encoding velocity, 75 cm/sec) before and after i.v. administration of an ACE inhibitor (enalaprilat). We analyzed velocity waveforms using established Doppler sonographic criteria. A timing examination with a test bolus of gadolinium contrast material was performed to ensure optimal arterial enhancement during breath-hold gadolinium-enhanced three-dimensional gradient-echo MR angiography. RESULTS: MR phase-contrast waveform pattern analysis was 50% (9/18) sensitive and 78% (40/51) specific for the detection of renal artery stenosis equal to or greater than 60% as shown on MR angiography. Sensitivity (67%, 12/18) and specificity (84%, 42/50) increased slightly, but not significantly, after i.v. administration of an ACE inhibitor. Also, the accuracy of quantitative criteria such as acceleration time and acceleration index did not improve after the administration of ACE inhibitor. CONCLUSION: Renal hilar velocity waveforms, measured using non-breath-hold MR phase-contrast techniques with or without an ACE inhibitor, are insufficiently accurate to use in predicting renal artery stenosis.

Adult↗
PubMed2000

Dynamic contrast-enhanced T2-weighted MR imaging of recurrent malignant gliomas treated with thalidomide and carboplatin.

BACKGROUND AND PURPOSE: Dynamic, contrast-enhanced MR imaging has allowed quantitative assessment of cerebral blood volume (CBV) in brain tumors. The purpose of our study was to compare postcontrast T1-weighted imaging with dynamic, contrast-enhanced T2*-weighted echo-planar imaging in the evaluation of the response of recurrent malignant gliomas to thalidomide and carboplatin. METHODS: Serial MR imaging was performed in 18 consecutive patients with recurrent malignant gliomas receiving both thalidomide and carboplatin for 12-month periods. Six patients undergoing carboplatin therapy alone were chosen as control subjects. Conventional postcontrast T1-weighted images were compared with relative CBV (rCBV) maps calculated on a pixel-by-pixel basis from dynamic echo-planar imaging data. Tumor progression was evaluated clinically using established criteria for malignant gliomas. Studies were performed at 2- to 3-month intervals, and imaging and clinical findings were compared. RESULTS: Tumor response to treatment, based on clinical findings, did not correlate well with conventional imaging findings. The rCBV values decreased significantly in all patients between the start of therapy and the first follow-up in the study group, but not in the control group. The difference in rCBV values between the clinically stable and the progressive group at 12-month follow-up was statistically significant, with the progressive group having higher values. CONCLUSION: Dynamic, contrast-enhanced MR imaging is a valuable adjunct to conventional imaging in assessing tumor activity during antiangiogenic therapy, and correlates better than conventional studies with clinical status and response to therapy.

Adult↗
PubMed1999

Brain endogenous insulin effects on neurite growth within fetal rat neuron cell cultures.

We have previously described insulin to be synthesized "de novo" within the fetal rat brain and that brain endogenous insulin [I(n)] promoted neurofilament distribution within fetal neurons. In this study, we investigated the role of I(n) in neuron axonal growth. Rat fetal brain stem cells from 16-day gestational age were cultured in an IFDM and treated with an insulin antibody. In addition, the cell cultures were also treated in defined medium with the addition of: 5 ng, 20 ng or 100 ng/ml of insulin or 100 ng/ml insulin-like growth factor 1 (IGF-1). The neuron cell cultures were studied at 1 and 3 days of incubation. The presence of preproinsulin mRNA and insulin immunoreaction confirmed the "de novo" synthesis of insulin by the fetal neuron cell cultures. Axonal growth was similar by day 1 of the study in all the media, but in insulin medium containing 100 ng/ml of insulin the axonal length was significantly longer. By day 3 of incubation I(n) promoted axonal growth. Treating the neurons with an insulin antibody confirmed these findings, with a significant decrease in axonal length (p<0.05). The treatment with different concentrations of exogenous insulin did not promote axonal growth beyond I(n) by day 3 of incubation. IGF-1 did not promote axonal growth by day 3 of incubation. In summary, I(n) may promote axonal growth during brain development.

Animals↗
PubMed1999

The balance between isoforms of the prickle LIM domain protein is critical for planar polarity in Drosophila imaginal discs.

The tissue polarity mutants in Drosophila include a set of conserved gene products that appear to be involved in the control of cytoskeletal architecture. Here we show that the tissue polarity gene prickle (pk) encodes a protein with a triple LIM domain and a novel domain that is present in human, murine, and Caenorhabditis elegans homologs which we designate PET. Three transcripts have been identified, pk, pkM, and sple, encoding 93-, 100-, and 129-kD conceptual proteins, respectively. The three transcripts span 70 kb and share 6 exons that contain the conserved domains. The pk and sple transcripts are expressed with similar tissue-specific patterns but have qualitatively different activities. The phenotypes of pk mutants, and transgenic flies in which the different isoforms are overexpressed show that the balance between Pk and Sple is critical for the specification of planar polarity. In addition, these phenotypes suggest a tessellation model in which the alignment of wing hairs is dependent on cell shape and need not reflect fine-grained positional information. Lack of both pk and sple transcripts gives a phenotype affecting the whole body surface that is similar to those of dishevelled and frizzled (fz) suggesting a functional relationship between pk and fz signaling.

Amino Acid Sequence↗
PubMed1999

Regulation of the photosynthetic electron transport chain.

The regulation of electron transport between photosystems II and I was investigated in the plant Silene dioica L. by means of measurement of the kinetics of reduction of P(700) following a light-to-dark transition. It was found that, in this species, the rate constant for P(700) reduction is sensitive to light intensity and to the availability of CO(2). The results indicated that at 25 degrees C the rate of electron transport is down-regulated by approximately 40-50% relative to the maximum rate achievable in saturating CO(2) and that this down-regulation can be explained by regulation of the electron transport chain itself. Measurements of the temperature sensitivity of this rate constant indicated that there is a switch in the rate-limiting step that controls electron transport at around 20 degrees C: at higher temperatures, CO(2) availability is limiting; at lower temperatures some other process regulates electron transport, possibly a diffusion step within the electron transport chain itself. Regulation of electron transport also occurred in response to drought stress and sucrose feeding. Measurements of non-photochemical quenching of chlorophyll fluorescence did not support the idea that electron transport is regulated by the pH gradient across the thylakoid membrane, and the possibility is discussed that the redox potential of a stromal component may regulate electron transport.Keywords: DeltapH. Electron transport. Photosynthesis. Photosynthetic control. Redox regulation. Silene (photosynthesis)

Journal Article↗
PubMed1999

The adhesion function on acetylcholinesterase is located at the peripheral anionic site.

There is accumulating evidence that acetylcholinesterase has secondary noncholinergic functions, related to adhesion, differentiation, and the deposition of beta-amyloid in Alzheimer's disease. We have observed that the specific acetylcholinesterase peripheral anionic site inhibitors, BW284c51 and propidium iodide, abrogated cell-substrate adhesion in three human neuroblastoma cell lines. The active-site inhibitors, eserine and edrophonium, in contrast, had no effect. Certain anti-AChE antibodies were also shown to inhibit adhesion. Of these, the most effective were a monoclonal (E8) and a polyclonal having cholinesterase-like catalytic activity. These were raised against an acetylcholinesterase-inhibitor complex, implying that the epitope is associated with active-site structures. Two other monoclonal antibodies (E62A1 and E65E8) partially inhibited adhesion. The epitopes of these antibodies have been shown to overlap the peripheral anionic site of acetylcholinesterase. Competition ELISA between the monoclonal antibodies and inhibitors indicated competition between E8, E62A1, and E65E8 and the peripheral-site inhibitors BW284c51 and propidium, but not with the active-site inhibitors eserine and edrophonium. Fluorescence titration between antibodies and propidium confirmed these results. We conclude that the adhesion function of acetylcholinesterase is located at the peripheral anionic site. This has implications, not only for our understanding of neural development and its disorders, but also for the treatment of neuroblastoma, the leukemias, and Alzheimer's disease.

Acetylcholinesterase↗
PubMed1999

MR perfusion imaging in human brain using the UNFAIR technique. Un-inverted flow-sensitive alternating inversion recovery.

Pulsed arterial spin labeling magnetic resonance techniques have been developed recently to estimate cerebral blood flow (CBF). Flow-sensitive alternating inversion recovery (FAIR) is one such technique that has been implemented successfully in humans. Un-inverted FAIR (UNFAIR) is an alternative technique in which the flow-sensitive image is acquired following inversion of all spins outside the slice of interest, and the control image is acquired without any spin labeling. This approach is potentially more efficient than FAIR since the UNFAIR control image is entirely flow independent and need only be acquired once. Here, we describe implementation of the sequence on a clinical 1.5 T magnetic resonance system. Both FAIR and UNFAIR perfusion-weighted images were obtained from six normal volunteers. Wash-in/wash-out curves measured in cortical gray and white matter were practically identical for the two techniques, as predicted by our model.

Adult↗
PubMed1999

2D multislice and 3D MRI sequences are often equally sensitive.

A simple theoretical model was developed to compare the sensitivities (i.e., signal-to-noise ratios per unit imaging time) of two-dimensional (2D) multislice and 3D imaging sequences. The model shows that the sensitivities of 3D and 2D multislice MRI sequences are usually similar. Sensitivities are identical in T2-weighted sequences when the T(R)s of the two sequences are the same. In T1-weighted gradient-echo sequences, sensitivities are very similar when Ernst angle excitation is used and the T(R) of the 2D sequence is less than T1. The predictions of the model are confirmed in phantom and animal experiments.

Animals↗
PubMed1999

Generation of the primary antibody repertoire in rabbits: expression of a diverse set of Igk-V genes may compensate for limited combinatorial diversity at the heavy chain locus.

In mouse and human, generation of combinatorial diversity through use of different heavy and light chain variable region genes in immunoglobulin rearrangements can be a major contributor to the primary antibody repertoire. In rabbits, the contribution of the combinatorial mechanism to heavy chain diversity is minimal, as only a few Igh-V genes are rearranged and expressed. To investigate the contribution of combinatorial diversity toward generation of the rabbit V(kappa) repertoire, we constructed five genomic libraries from rabbit kidney DNA and 1 cDNA library from the bone marrow of a 1-day-old rabbit using a series of polymerase chain reaction-based strategies. Our analyses indicate that most of the sequences that we recovered from our libraries belong to a single family and some are extremely similar. The actual number of germline Igk-V genes is potentially greater than our conservative estimate of at least 39, 28 of which we found expressed as mRNA. The germline Igk-V genes display different lengths of the coding region 3' of Cys 88 ranging from 7 to 12 amino acids, resulting in CDR3 length heterogeneity among functional V(kappa)J(kappa) sequences ranging from 8 to 15 amino acids. Some of the V(kappa)J(kappa) junctions had N and P nucleotide additions. Thus, in contrast to limited combinatorial diversity of its heavy chain, the rabbit can draw upon a diverse set of germline Igk-V genes. The kappa light chain has the potential to be a major contributor toward generation of the antibody specificities of the rabbit pre-immune repertoire.

Amino Acid Sequence↗
PubMed1999

Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. Vasodilator-Heart Failure Trial Study Group.

BACKGROUND: Heart failure in blacks has been associated with a poorer prognosis than in whites. In such diseases as hypertension, blacks show pathophysiological differences and respond differently to some therapies than whites. The aim of this study is to evaluate the clinical characteristics and response to therapy of black compared with white patients with heart failure. METHODS AND RESULTS: In the first Vasodilator-Heart Failure Trial (V-HeFT I), 180 black male patients were compared with 450 white male patients for baseline characteristics, prognosis, and response to therapy. In V-HeFT II, the same comparisons were made for 215 black and 574 white male patients, including an analysis stratified by the presence or absence of a history of hypertension. In both trials, black patients had a lower incidence of coronary artery disease, greater incidence of previous hypertension, and a greater cardiothoracic ratio (P < .05) than white patients. In V-HeFT II, plasma norepinephrine levels were significantly less in blacks; plasma renin activity was less only in blacks with a history of hypertension. Overall mortality or hospitalization for congestive heart failure did not differ between blacks and whites in the placebo group in V-HeFT I. However, the mortality of black patients receiving hydralazine plus isosorbide dinitrate (H-I) was reduced (P = .04) in V-HeFT I, whereas white patients showed no difference from placebo. In V-HeFT II, only white patients showed a mortality reduction from enalapril therapy compared with H-I therapy (P = .02). Whites also showed evidence of greater blood pressure reduction and enhanced regression of cardiac size in response to enalapril. When stratified by history of hypertension in V-HeFT II, only whites with a history of hypertension, who had greater renin levels, showed significant mortality reduction with enalapril compared with H-I therapy. Hospitalization rates did not differ between treatment groups in either study. CONCLUSION: Whites and blacks showed differences in cause, neurohormonal stimulation, and pharmacological response in heart failure. This retrospective analysis suggests angiotensin-converting enzyme inhibitors are particularly effective in whites, and the H-I combination can be equally effective in blacks. Prospective trials involving large numbers of black patients are needed to further clarify their response to therapy.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1999

Retinal manifestations of HIV-1 and HIV-2 infections among hospital patients in The Gambia, west Africa.

BACKGROUND: In developed countries, 50-75% of AIDS patients develop retinal complications and about 20-40% acquire cytomegalavirus (CMV) retinitis. We conducted a cross-sectional survey to determine prevalence of these in The Gambia where both HIV-1 and HIV-2 infection are present and the prevalence of HIV-1 is rising. METHOD: All patients attending hospital whose percentage CD4+ cells (CD4%) was below 14, the level associated typically with an AIDS diagnosis, and one half of those whose CD4% was 14 or above were asked to join the study. Fifty-six HIV-1, 52 HIV-2 and 12 dually infected patients were recruited. Photographs of the fundi were taken and interpreted independently. The findings were related to the patients' percentage CD4+ cells. RESULTS: The CD4% was < 14 in 40 patients and < 7 in 17 patients. Thirty-six patients were male. No cases of CMV retinitis were found. Four patients whose CD4% were 4, 5, 11 and 23 had cotton wool spots ranging in number from 1 to 14 for any one patient. The prevalence of cotton wool spots was 8% (95% CI, 0-16%) among patients with CD4% below 14 and 12% (95% CI, 0-27) among patients with CD4% below 7. One of the 4 patients had associated microaneurysm and blot haemorrhages typical of more advanced HIV microvasculopathy. CONCLUSION: CMV retinitis is less common in The Gambia than in developed countries. Non-infectious retinopathy may also be less common.

AIDS-Related Opportunistic Infections↗