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J Myklebust

Publications and source records attributed to J Myklebust.

At least 19 recordsLinked to original sources
PubMed2000

Quantitative trait loci on chromosomes 3 and 17 influence phenotypes of the metabolic syndrome.

Recent research has emphasized the importance of the metabolic cluster, which includes glucose intolerance, dyslipidemia, and high blood pressure, as a strong predictor of the obesity-related morbidities and premature mortality. Fundamental to this association, commonly referred to as the metabolic syndrome, is the close interaction between abdominal fat patterning, total body adiposity, and insulin resistance. As the initial step in identifying major genetic loci influencing these phenotypes, we performed a genomewide scan by using a 10-centiMorgan map in 2,209 individuals distributed over 507 nuclear Caucasian families. Pedigree-based analysis using a variance components linkage model demonstrated a quantitative trait locus (QTL) on chromosome 3 (3q27) strongly linked to six traits representing these fundamental phenotypes [logarithm of odds (lod) scores ranged from 2.4 to 3.5]. This QTL exhibited possible epistatic interaction with a second QTL on chromosome 17 (17p12) strongly linked to plasma leptin levels (lod = 5.0). Situated at these epistatic QTLs are candidate genes likely to influence two biologic precursor pathways of the metabolic syndrome.

Blood Glucose↗
PubMed1999

Lovastatin inhibits G1/S transition of normal human B-lymphocytes independent of apoptosis.

Lovastatin is a potent inhibitor of protein prenylation, and it has been reported to have pleiotropic cellular effects. In the present study we have elucidated the effects of lovastatin on cell cycle progression and apoptosis of normal human B-lymphocytes. When added to B-lymphocytes stimulated with anti-immunoglobulin (anti-mu) and SAC, lovastatin (20 microM) inhibited the cells in the late G1 phase of the cell cycle. Thus, no early activation parameters such as Ca(2+) flux or MYC induction were affected by lovastatin, whereas progression of cells into the second cell cycle as well as DNA synthesis was markedly reduced. We therefore examined the effects of lovastatin on components of the cell cycle machinery responsible for regulating the G1/S transition. We demonstrated that pRB phosphorylation, cdk2 activity needed for this phosphorylation, and the levels of cyclin A, D, and E were inhibited after 24 h of lovastatin treatment, while the levels of p27(Kip1) were elevated. There was no effect on p21(Cip1), cyclin D2, cdk4, and cdk6. These data are consistent with the cells being inhibited by lovastatin between 24 and 32 h into G1. Lovastatin added to stimulated B-cells in late G1 still inhibited the DNA synthesis by 60%, but at this point only minor effects were noted on the cell cycle machinery. We therefore looked for induced apoptosis as an explanation for reduced S-phase entry of the cells. However, despite the ability to enhance the apoptosis of unstimulated B-cells from 48 to 61% as judged by the TUNEL method, lovastatin only marginally affected apoptosis when administered to stimulated B-cells. Thus, it appears that accelerated apoptosis cannot account for the effect of lovastatin on cell cycle progression.

Apoptosis↗
PubMed1997

Cytotoxic CD4+ and CD8+ T lymphocytes, generated by mutant p21-ras (12Val) peptide vaccination of a patient, recognize 12Val-dependent nested epitopes present within the vaccine peptide and kill autologous tumour cells carrying this mutation.

Mutant p21-ras proteins contain sequences that distinguish them from normal ras, and represent unique epitopes for T-cell recognition of antigen-bearing tumour cells. Here, we examined the capacity of CD4+ and CD8+ T cells, generated simultaneously by mutant-ras-peptide vaccination of a pancreatic-adenocarcinoma patient, to recognize and lyse autologous tumour cells harbouring corresponding activated K-ras epitopes. The patient was vaccinated with a purified 17mer ras peptide (KLVVVGAVGVGKSALTI), containing the Gly12 --> Val substitution. Responding T cells were cloned following peptide stimulation, and CD4+ and CD8+ peptide-specific cytotoxic T lymphocytes(CTL) were obtained. Transient pancreatic-adenocarcinoma cell lines(CPE) were established in cell culture from malignant ascites of the patient, and were shown to harbour the same K-ras mutation as found in the primary tumour. These cells were efficiently killed by the T-cell clones and CD8+-mediated cytotoxicity was HLA-class-I-restricted, as demonstrated by inhibition of lysis by anti-class-I monoclonal antibodies. By employing as targets different class-I-matched tumour cell lines expressing a 12Val mutation, we were able to demonstrate HLA-B35 as the restriction molecule, and further use of peptide-sensitized EBV-B cells as target cells identified VVVGAVGVG as the nonamer peptide responsible for CD8+-T-cell recognition. These data demonstrate that peptide vaccination with a single mutant p21-ras-derived peptide induces CD4+ and CD8+ CTL specific for nested epitopes, including the Gly --> Val substitution at codon 12, and that both these T-cell sub-sets specifically recognize tumour cells harbouring the corresponding K-ras mutation.

Adenocarcinoma↗
PubMed1996

Ability of flt3 ligand to stimulate the in vitro growth of primitive murine hematopoietic progenitors is potently and directly inhibited by transforming growth factor-beta and tumor necrosis factor-alpha.

The recently cloned flt3 ligand (FL) stimulates the growth of primitive hematopoietic progenitor cells through synergistic interactions with multiple other cytokines. The present study is the first demonstrating cytokines capable of inhibiting FL-stimulated hematopoietic cell growth. Tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta 1 (TGF-beta l) potently inhibited the clonal growth of murine Lin-Sca-l+ bone marrow progenitors stimulated by FL alone or in combination with granulocyte colony-stimulating factor (G-CSF), stem cell factor (SCF), interleukin (IL)-3, IL-6, IL-11, or IL-12. TGF-beta 1 inhibited more than 96% of the myeloid colony formation in response to these cytokine combinations, whereas TNF-alpha reduced the number of colonies by 58% to 96% depending on the cytokine by which FL was combined. In addition, both TNF-alpha and TGF-beta 1 inhibited more than 90% of B220+ cell production from B220- bone marrow cells stimulated by FL + IL-7. The effects of TNF-alpha and TGF-beta 1 appeared to be due to a direct effect and on the early progenitors because the inhibition was observed at the single cell level, and because delayed addition of the two inhibitors for only 48 hours dramatically reduced their inhibitory effects. A neutralizing anti-TGF-beta antibody showed the presence of endogenous TGF-beta in the cultures and potently enhanced the ability of FL to stimulate progenitor cell growth in the absence of other cytokines. Agonistic antibodies specifically activating the p75 TNF receptors were more efficient than wild type murine TNF-alpha in signaling growth inhibition of Lin-Sca-l+ progenitor cells, whereas the p55 agonist had less effect than murine TNF-alpha. Finally, TGF-beta increased the number of FL + IL-11-stimulated Lin-Sca-1+ cells in the G1 phase of the cell cycle with 76%, whereas TNF-alpha only had a marginal effect on cell cycle distribution. Thus, TGF-beta, TNF-alpha, and p75 TNF receptor agonists are potent direct inhibitors of FL-stimulated progenitor cell growth in vitro.

Animals↗
PubMed1995

The FLT3 ligand potently and directly stimulates the growth and expansion of primitive murine bone marrow progenitor cells in vitro: synergistic interactions with interleukin (IL) 11, IL-12, and other hematopoietic growth factors.

The recently cloned murine flt3 ligand (FL) was studied for its ability to stimulate the growth of primitive (Lin-Sca-1+) and more committed (Lin-Sca-1-) murine bone marrow progenitor cells, alone and in combination with other hematopoietic growth factors (HGFs). Whereas FL was a weak proliferative stimulator alone, it potently synergized with a number of other HGFs, including all four colony-stimulating factor (CSF), interleukin (IL) 6, IL-11, IL-12, and stem cell factor (SCF), to promote the colony formation of Lin-Sca-1+, but not Lin-Sca-1- or erythroid progenitor cells. The synergistic activity of FL was concentration dependent, with maximum stimulation occurring at 250 ng/ml, and was observed when cells were plated at a concentration of one cell per culture, suggesting that its effects are directly mediated. 2 wk of treatment with FL in combination with IL-3 or SCF resulted in the production of a high proportion of mature myeloid cells (granulocytes and macrophages), whereas the combination of FL with G-CSF, IL-11, or IL-12 resulted predominantly in the formation of cells with an immature blast cell appearance. Accordingly, FL in combination with G-CSF or IL-11 expanded the number of progenitors more than 40-fold after 2 wk incubation. Thus, FL emerges as a potent synergistic HGF, that in combination with numerous other HGFs, can directly stimulate the proliferation, myeloid differentiation, and expansion of primitive hematopoietic progenitor cells.

Animals↗
PubMed1994

Electric field distribution within normal cat spinal cord.

Electric currents of small magnitude have been used successfully to induce regrowth of injured spinal cord fibers. The purpose of this study was to determine the potentials and current density distributions on the surface, as well as within the spinal cord, after the application of exogenous electric fields. A 10 microA DC current was applied epidurally to the spinal cord using two different electrode configurations. The two electrode configurations studied were: anode and cathode dorsal (D-D) and anode ventral and cathode dorsal (V-D). Two types of recording electrodes were used to map the potentials on the surface and within the spinal cord. The recording system consisted of glass microelectrodes connected to differential amplifiers. The output was recorded on a polygraph. The current density was more localized on the dorsal surface of the spinal cord for the D-D configuration. In contrast, in the V-D configuration, the current density was greater near the anode on the ventral surface and near the cathode on the dorsal surface of the spinal cord. As a result of the anode being located ventrally, there was a more uniform current density distribution within the spinal cord.

Animals↗
PubMed1994

Electrical field distribution within the injured cat spinal cord: injury potentials and field distribution.

This study investigated the spontaneous injury potentials measured after contusion or transection injury to the cat spinal cord. In addition, the distribution of electrical field potentials on the surface and within the spinal cord were measured following applied electrical fields after transection and contusion injuries. After transection of the spinal cord, the injury potentials were -19.8 +/- 2.6 mV; after contusion of the spinal cord, the injury potentials were -9.5 +/- 2.2 mV. These potentials returned to control values within 2.5-4h after injury. The electrical field distribution measured on the dorsal surface, as well as within the spinal cord, after the application of a 10 microA current, showed little difference between contusion and transection injuries. Scalar potential fields were measured using two configurations of stimulating electrodes: dorsal to dorsal (D-D), in which both electrodes were placed epidurally on the dorsal surface of the spinal cord, and ventral to dorsal (V-D), in which one electrode was placed dorsally and one ventrally. As reported in normal uninjured cats, the total current in the midsagittal plane for the D-D configuration was largely confined to the dorsal portion of the spinal cord; with the V-D configuration, the current distribution was uniform throughout the spinal cord. In the injured spinal cord, the equipotential lines midway between the stimulating electrodes have a wider separation than in the uninjured spinal cord. Because the magnitude of the electrical field E is equal to the current density J multiplied by the resistivity r, this suggests that either the current density is reduced or that the resistivity is reduced.

Animals↗
PubMed1988

Biomechanics of cervical spine facetectomy and fixation techniques.

Facetectomy, either unilateral or bilateral, significantly altered the capacity of cervical spine functional units to withstand increasing compression-flexion loads applied in a constant mode to different specimen configurations. Unilateral facetectomy resulted in an average 31.6 +/- 9.7 percent decrease in strength whereas bilateral disruption caused an average 53.1 +/- 11 percent decrease in strength. Motion analysis in a two-dimensional plane after facetectomy indicated an anterior displacement of the instantaneous axis of rotation (IAR) with a resultant increased load on the vertebral bodies and disc. This anterior shift of the IAR in the horizontal plane was significantly but not completely resolved by wire fixation of the facet joints. These fixation techniques, consisting of either facet to facet or facet to spinous process wiring, demonstrated a similar capability to restore strength to the functional units as well as reducing excessive motion in the vertical and anterior axes induced by the facetectomies.

Aged↗
PubMed1985

Measure of tissue resistivity in experimental electrical burns.

Studies were conducted in 14 mongrel dogs to compare resistivities in normal muscle with those from muscle subjected to electrical burns. One-ampere, 60-Hz currents were passed between the hind limbs of the dogs producing injury in three measurement regions of the gracilis muscle. Histology, heart rate, body temperature, arterial and pulmonary artery pressure, cardiac output, hematocrit, leukocyte counts, fibrinogen levels, and platelet levels were determined. Muscle resistivity associated with severe tissue necrosis was 70% lower than control values. Resistivity in tissue showing edema and minimal necrosis decreased 20 to 40% from control values. Muscle showing only edema had a 10 to 30% decrease in resistivity.

Animals↗
PubMed1982

Effects of vertebral column distraction in the monkey.

Experiments were performed to assess the effects of vertebral column distraction on evoked potential responses from multiple recording sites along the conducting pathway in the monkey, and on concurrent blood flows, measured with the radioactive microsphere technique, along the axis of the central nervous system. Linear distractive loads were applied until the amplitude of the evoked response was significantly reduced. In four monkeys, the loads (100 to 150 lb) were sustained, whereas in two monkeys the forces (80 to 110 lb) were relaxed. The earliest response changes were most marked in recordings dependent upon the integrity of the upper cervical dorsal columns or brain stem-lemniscal pathway. The responses returned to control levels with load relaxation, but maintenance of the tractive load produced generalized and progressive response attenuation. At selected periods of significant changes in the evoked potential response, blood flow remained stable except for the late onset of regional ischemia in the middle cervical through upper thoracic spinal cord levels in the animals undergoing sustained loads. These findings indicate that brain-stem or spinal cord dysfunction occurring with both acute and gradual elongation of the spinal canal are the result of excess tensile stress acting on fiber tracts, and the delayed onset of spinal cord ischemia is the probable result of a similar mechanical process acting upon intrinsic spinal cord blood vessels.

Animals↗
PubMed1980

Effect of electrical current on temperature and pH in cerebellum and spinal cord.

Electrical currents similar to those used for relief of pain and spasticity were applied to the spinal cord and cerebellum of monkeys and cats. Direct coupled monopolar pulses increased pH at the tissue surface near a negative electrode and correspondingly decreased the pH near a positive electrode. Cerebrospinal fluid (CSF) circulation around the electrodes neutralized these changes. Capacitively coupled currents up to a 10 mA peak and 2.5 mucoul per peak failed to change tissue pH measurably. Current levels with power densities of 100 mW per cm2 did not cause any change in tissue temperature.

Animals↗
PubMed1978

Evoked potential measurement and analysis on a small laboratory computer.

A program is described for the collection and subsequent analysis of somatosensory evoked potentials using a LINC-8 computer. The program allows simple evoked-potentials analysis in centers where a small laboratory computer may be available but sophisticated instrumentation such as a computer of average transients is not available. This program provides an efficient method of easily obtaining information concerning the conduction pathways of the nervous system as well as the cerebral function; the program can be implemented on small laboratory computers which most hospitals currently own, without the associated cost or complexity of additional hardware in the laboratory. Combining utilization of a small laboratory computer with an easily programmable method provides an approach for evoked potential analysis which is well within the financial and technical scope of most neurophysiology laboratories.

Computers↗
PubMed1978

Early somatosensory evoked potentials.

The early somatosensory evoked potential secondary to median nerve stimulation in the human had an onset latency of 9--12 msec when recorded from scalp electrodes at vertex-to-mastoid, vertex-to-inion or at the base of the skull. Similar latencies were observed from responses recorded over the cervical dorsal columns during neurologic surgery. A latency difference of 1.5 msec was observed between the early response and the responses recorded from the junction of medial lemniscus and nucleus ventralis posterior lateralis of the thalamus during human stereotaxic surgery. Cervical cord transections and transection at the midpontine levels of the monkey showed that the evoked potential was due to generators between these levels. Depth recording of the monkey indicate that the early evoked potential originates in the region of dorsal column nuclei, while the later components are secondary to generators in cerebral cortex.

Animals↗
PubMed1978

Spinal evoked potentials in the primate: neural substrate.

Summated responses evoked by peripheral nerve stimulation were recorded from electrodes located in the epidural and subdural spaces anterior and posterior to the monkey spinal cord. Segmental microsurgical resection of the dorsal columns both at the thoracic and cervical levels resulted in total obliteration of the response recorded rostral to these lesions. Isolated segmental dorsal column preservation did not significantly alter response latency or wave form recorded at the rostral electrodes. Bilateral cervical dorsolateral column resection also resulted in no discernible alterations of these responses. These data indicate that spinal evoked potentials recorded from levels rostral to their root entry zones arise almost exclusively from the dorsal columns.

Animals↗
PubMedDate not supplied

Determination of tissue viability in experimental electrical injuries.

Electrical burns or ischemia (induced by vascular ligation) were produced in the legs of 15 anesthetized dogs to study evolution of tissue changes compared with impedance alterations. After the application of 1-ampere currents at 60 Hz, animals were monitored from 1 to 4 days. Muscle impendance was measured with frequency sweeping to determine tissue destruction. Nuclear magnetic resonance spectroscopy (phosphorus 31) was used to assess metabolic activity, and results were compared to impedance measurements. In burned limbs, 70% reduction in muscle impedance was seen, which corresponds to decreased metabolic activity (absent organic phosphates) and suggests necrosis. Visually viable tissue had impedance decreases of 25% and levels of organic phosphates slightly lower than normal. Relaxation frequencies in dogs with severe burns exceeded 80 kHz; in viable tissue, 30 to 40 kHz (normal: 30 kHz). In ischemic muscle, organic phosphates decreased rapidly (1 to 2 hours); impedance changes evolved more slowly (1 day), but they ultimately reached the same degree of severity. Measurement of impedance may be a valuable adjunct in the evaluation of electrical burns, since significant changes strongly suggest nonviability.

Animals↗