A simple methodology to improve AIS-based assessment of recovery after acute spinal cord injury.
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Acute Disease↗
Biomedical subjects
R Jaeger
Publications and source records attributed to R Jaeger.
Otolith responses to dynamical stimuli: results of a numerical investigation.
To investigate the dynamic effects of external forces on the displacement of the otolith membrane and subsequent neuronal responses of otoliths, we performed numerical analyses of otolith membrane displacements. In these studies we included the full geometry of the human otolith maculae, including their 3D curvature. The first part focuses on mechanical aspects of the otolith membrane. While it was found that the mechanical coupling of distant parts of the otolith membrane is only weak, these simulations indicate that curvature may have considerable local effects on displacements. They further suggest that the movements of the otoconia, embedded in the interotoconial matrix, show a resonance in a range between 100 and 2000 Hz. In the second part of the article we also investigate the tonic-phasic responses in the vestibular nerve emanating from hair cells in the striola region. Small head tilts away from head upright position are used. The simulations indicate that the direction of head tilt is coded in characteristic response patterns along the striola.
Computer Simulation↗
Modeling the relation between head orientations and otolith responses in humans.
We have performed a finite element simulation of realistic displacements of otolith membranes by static linear accelerations. The simulations were based on accurate measurements of the surfaces of human utricular and saccular maculae, which indicate a clear curvature of these surfaces. The results show that this curvature, a feature probably found in all mammals, has no effect on the mechanics of the structure as a whole since the elastic coupling in the otolith membrane is insufficient. Hair cell excitations on any place of the macula are only affected by the local orientation of the macula with respect to acceleration. Based on the displacements of the otolith membrane, we also calculated the induced activation patterns on the otolith epithelia. These patterns provide for the first time a complete image of peripheral otolith activity. The individual activation patterns at selected locations on the macula correspond well with single cell recordings of actual peripheral otolith neurons.
Cell Polarity↗
Inhibition by guanosine cyclic monophosphate (cGMP) analogues of uptake of [(3)H]3',5'-cGMP without stimulation of ATPase activity in human erythrocyte inside-out vesicles.
The cellular extrusion of guanosine 3',5'-cyclic monophosphate (3',5'-cGMP) is a unidirectional ATP-dependent process that is inhibited by probenecid, a non-selective transport inhibitor of organic anions. In the present study, various cGMP analogues were tested for their ability to inhibit 3',5'-cGMP efflux and stimulate the cGMP-selective ATPase in human erythrocytes. The difference in uptake of 1 microM [(3)H]3',5'-cGMP to inside-out vesicles in the presence and absence of 1 mM ATP at 37 degrees was defined as active transport. Two ATP-dependent components were detected for unlabelled 3',5'-cGMP (0.01--100 microM) with respective K(i) of 1.3 +/- 0.2 and 280 +/- 50 microM (mean +/- SEM, N = 3). The high-affinity transport was inhibited by the analogues with a typical pattern: Rp-monophosphorothioate guanosine 3',5'-cyclic monophosphate (Rp-cGMPS) > 3',5'-cGMP > 2'-O-monobutyryl guanosine 3',5'-cyclic monophosphate (O-mb-cGMP) approximately N(2)-monobutyryl guanosine 3',5'-cyclic monophosphate (N-mb-cGMP) > or = N(2),2'-O-dibutyryl guanosine 3',5'-cyclic monophosphate (Db-cGMP) approximately 8'-bromo guanosine 3',5'-cyclic monophosphate (Br-cGMP) approximately Guanosine 2',3'-cyclic monophosphate (2'3'-cGMP) > Sp-monophosphorothioate guanosine 3',5'-cyclic monophosphate (Sp-cGMPS). A concentration-dependent inhibition was found for the low-affinity transport, but no distinct order of potency was identified. Analysis according to Lineweaver--Burk of active [(3)H]3',5'-cGMP transport (0.2--2 microM) gave a K(m) value of 1.5 +/- 0.1 microM (mean +/- SEM, N = 3). The presence of 10 microM cGMP analogues did not change the ordinate intercept, but made the slopes steeper with a typical order: Rp-cGMPS > 3',5'-cGMP > N-mb-cGMP approximately O-mb-cGMP approximately db-cGMP approximately 8-Br-cGMP > 2',3'-cGMP > Sp-cGMPS. Only 3',5'-cGMP and 2',3'-cGMP were able to activate the cGMP-specific ATPase, 640 +/- 200% and 430 +/- 160% (mean +/- SEM, N = 5) above basal levels, respectively. The present data show that the binding is less selective than ATPase activation of the cellular cGMP transport system.
Adenosine Triphosphatases↗
Leukotriene C(4) (LTC(4)) does not share a cellular efflux mechanism with cGMP: characterisation of cGMP transport by uptake to inside-out vesicles from human erythrocytes.
The transport of cGMP out of cells is energy requiring and has characteristics compatible with an ATP-energised anion pump. In the present study a model with inside-out vesicles from human erythrocytes was employed for further characterisation of the cGMP transporter. The uptake of leukotriene C(4) (LTC(4)), a substrate for multidrug resistance protein (MRP), was concentration-dependently inhibited by the leukotriene antagonist MK571 (IC(50)=110+/-20 nM), but cGMP was unable to inhibit LTC(4) uptake. Oxidised glutathione (GSSG) and glutathione S-conjugates caused a concentration-dependent inhibition of [(3)H]cGMP uptake with IC(50) of 2200+/-700 microM for GSSG, 410+/-210 microM for S-(p-nitrobenzyl)glutathione and 37+/-16 microM for S-decylglutathione, respectively. Antioxidants such as reduced glutathione and dithiothreitol did not influence transport for concentrations up to 100 microM, but both inhibited cGMP uptake with approx. 25% at 1 mM. The cGMP pump was sensitive to temperature without activity below 20 degrees C. The transport of cGMP was dependent on pH with maximal activity between pH 8.0 and 8.5. Calcium caused a concentration-dependent inhibition with IC(50) of 43+/-12 microM. Magnesium gave a marked activation in the range between 1 and 20 mM with maximum effect at 10 mM. The other divalent cations, Mn(2+) and Co(2+), were unable to substitute Mg(2+), but caused some activation at 1 mM. EDTA and EGTA stimulated cGMP transport concentration-dependently with 50% and 100% above control at 100 microM, respectively. The present study shows that the cGMP pump has properties compatible with an organic anion transport ATPase, without affinity for the MRP substrate LTC(4). However, the blockade of the cGMP transporter by glutathione S-conjugates suggests it is one of several GS-X pumps.
Adenosine Triphosphate↗
Three-dimensional eye-movement responses to off-vertical axis rotations in humans.
We recorded three-dimensional eye movements elicited by velocity steps about axes that were tilted with respect to the earth-vertical. Subjects were accelerated in 1 s from zero to 100 degrees/s, and the axis of rotation was tilted by 15 degrees, 30 degrees, 60 degrees, or 90 degrees. This stimulus induced a constant horizontal velocity component that was directed opposite to the direction of rotation, as well as a modulation of the horizontal, vertical and torsional components with the frequency of the rotation. The maximum steady-state response in the horizontal constant-velocity component was much smaller than in other species (about 6 degrees/s), reaching a maximum at a tilt angle of about 60 degrees. While the amplitude of the horizontal modulation component increased up to a tilt angle of 90 degrees (8.4 degrees/s), the vertical and torsional modulation amplitudes saturated around 60 degrees (ca. 2.5 degrees/s). At small tilt angles, the horizontal modulation component showed a small phase lag with respect to the chair position, which turned into a small phase lead at large tilt angles. The torsional component showed a phase lead that increased with increasing tilt angle. The vertical and torsional velocity modulation at large tilt angles was not predicted by a recent model of otolith-canal interaction by Merfeld. Agreement between model and experimental data could be achieved, however, by introducing a constant force along the body's z-axis to compensate for the gravitational pull on the otoliths in the head-upright position. This approach had been suggested previously to explain the direction of the perceived subjective vertical during roll under different g-levels, and produced in our model the observed vertical and torsional modulation components at large tilt angles.
Adult↗
A novel cell line that retains the morphological characteristics of the cells and matrix of odontogenic myxoma.
Little is known about the histogenesis of the human odontogenic myxoma or the relation between tumour cells and the matrix. In order to attempt to remedy this situation, we established and investigated a cell line derived from a human odontogenic myxoma. To our knowledge this is the first cell line derived from this tumour. The cell line, named Mix 1, preserved features of the tumour cells. Mix 1 cells expressed vimentin, type I collagen, fibronectin, tenascin and hyaluronic acid. Ultrastructural analysis of cells of the tumour and cell line demonstrated similarities, both containing Golgi apparatus, rough endoplasmic reticulum and mitochondria indicative of secretory cells. Ultrastructural analysis showed the matrix to be represented by bundles of collagen fibrils in the tumour, and by irregular filaments in cultures more than 60 days old. The Mix 1 cell line promises to be an excellent model for investigating the biology of the odontogenic myxoma.
Adult↗
Functional electrical stimulation of abdominal muscles to augment tidal volume in spinal cord injury.
Functional electrical stimulation (FES) of abdominal muscles as a method of enhancing ventilation was explored in six neurologically intact subjects and five subjects with spinal cord injury (SCI) who had levels of injury between C4 and C7. Pulmonary ventilation was augmented in both groups predominantly due to an increase in tidal volume. The average increase in tidal volume during FES for the neurologically intact group was 350 ml, while in the SCI group it was 220 ml. The FES caused active volume decreases in both the lower thorax and upper abdomen, which together appear to be the mechanism behind the increases seen in tidal volume. Therefore, the proposed method might be useful in future clinical practice. The results indicate that FES of abdominal muscles should be more thoroughly explored as a potential technique of ventilatory support in SCI. The results also point to the necessity for further studies of maintaining the condition of the chest wall in the pulmonary rehabilitation of individuals with tetraplegia.
Abdominal Muscles↗
Otolith-canal interaction during pitch while rotating.
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Adult↗
Characterization of the cellular component of polymorphous low-grade adenocarcinoma by immunohistochemistry and electron microscopy.
In order to characterize the cellular component of the polymorphous low-grade adenocarcinoma (PLGA) of the salivary gland, a morphological and immunohistochemical study was carried out. Thirty cases of PLGA were studied by light microscopy and immunohistochemistry and five cases by transmission electron microscopy (TEM). The expression of cytokeratins (CKs) 7,8,10,13,14,18,19, vimentin and muscle-specific actin (MSA) was investigated through the streptavidin-biotin method. The majority of tumor cells stained for vimentin, CKs 8, 18 and 7. CK 14 was positive in most cells of the papillary and trabecular sub-types. Although the expression of CKs 8,18 and 14 varied among the tumors sub-types, a straight relationship between each histologic pattern and the CK expression could not be delineated. MSA was reactive in only three tumors while CKs 10 and 13 were not detected in any tumor studied. The absence of MSA and the expression of CKs 8,18 and 7, in most of the tumor cells, lead to the hypothesis that myoepithelial cells are not the major cellular component of the PLGA. TEM revealed cells exhibiting microvilli and variable amounts of secretory granules, some of them suggesting an excretory activity. The presence of CKs 8,18 and 7, added to the secretory granules, indicates that PLGA originates from cells located at the acinar-intercalated duct junction.
Adenocarcinoma↗
Structural elements common to mitosis and apoptosis.
Both mitotic and apoptotic cells display hypercondensation of the chromatin and loss of the nuclear envelope (Lazebnik et al., 1993). Herein, we describe a third similarity between the two processes. We have observed, initially in apoptotic cells of the PC-12 lineage clusters of 40-60 (approximately 50) nm vesicles adjoined by a minor contingent of tubule vesicular elements of 100-200 nm which are indistinguishable from their vesicular counterparts in mitotic PC-12 cells. The clusters of approximately 50 nm vesicles were subsequently observed in all studied rat tissue cells in apoptosis (plasma cells and macrophages, secretory epithelial cells from pancreatic acini, ventral lobe of prostate and mammary gland). Clusters of approximately 50 nm vesicles comparable to those of the PC-12 cells were found in HeLa cells treated with human alfa TNF, in WEHI-3 cells exposed to VM 26 (a teneposide) (Sesso et al., 1997) and in HL-60 cells treated with thapsigargin. PC-12 and HeLa cells affixed to coverslips were double labelled and examined with the fluorescence microscope to reveal simultaneously the disposition of the chromatin with Hoechst stain and the distribution of the fluorescence of Golgi or of Golgi-associated proteins. A common pattern of fluorescence was observed in a minor proportion of apoptotic cells using three different antibodies used. The label frequently appeared as finely dispersed granules in the cytoplasm. In some apoptotic cells, relatively coarse granules were observed. This pattern of label distribution is compatible with the disposition of vesicular clusters we have encountered in apoptotic PC-12 cells sectioned serially or semi serially. In such sections of both mitotic and apoptotic PC-12 cells, we noticed that the conglomerates of 50 nm vesicles were frequently associated with cisternae of the rough ER. Vesicles of similar size were also noted pinching off from the extremities of Golgi cisternae reduced in size. These cisternae diminish in length and width when they are in the process of disassembling at the very beginning of mitosis and in apoptosis.
Animals↗
Polysulfated heparinoids selectively inactivate heparin-binding angiogenesis factors.
Angiogenesis is a prerequisite for tumor expansion and metastasis. The angiogenic potential of the heparin-binding growth factors acidic fibroblast growth factor (FGF) and basic FGF has been demonstrated in various publications. We studied the inhibitory effects of suramin and the polysulfated heparinoids pentosan polysulfate, dextran sulfate, and fucoidan on the action of FGF. As an experimental model, we used the adrenal cancer cell line SW 13, whose anchorage-independent growth depends on the presence of FGF. The polysulfated heparinoids inhibited FGF-induced growth and binding to the receptor at an IC50 of 0.5-3 micrograms/ml. Suramin inhibited FGF at an IC50 of 100 micrograms/ml. The polysulfated heparinoids exerted no effect on IGF-1 or TGF alpha-related growth. Suramin inhibited the anchorage-independent growth induced by IGF-1 or TGF alpha only at an IC50 of 100 micrograms/ml. Our results indicate that suramin inhibits growth factors in a nonselective way. By contrast, polysulfated heparinoids exert a selective inhibitory effect on heparin binding angiogenesis factors at an IC50, which is 100 times below the IC50 of suramin. Therefore, the administration of polysulfated heparinoids might become a novel approach to tumor therapy based on blocking angiogenesis.
Binding, Competitive↗
Urinary levels of cyclic guanosine monophosphate (cGMP) in patients with cancer of the uterine cervix: a valuable prognostic factor of clinical outcome?
Changes in urinary cyclic nucleotide levels have been reported in patients with various types of cancers. The present study was conducted to relate changes in urinary levels of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) to the clinical outcome of 11 patients treated for cancer of the uterine cervix. Urine was sampled for 24 h before and 3 months after primary treatment. The levels of cGMP increased in all the patients (n = 5) who relapsed within the observation period of 39 months. 4 of these patients showed an increased cGMP/cAMP ratio. In the patients without relapse (n = 6), the cGMP levels decreased, whereas the cGMP/cAMP ratios were unchanged. No marked changes in the levels of cAMP were observed for either of the groups. The measurement of urinary cGMP levels seems to be a valuable tool in the follow-up of patients with cancer of the uterine cervix.
Adult↗
Apoptosis in the terminal endbud of the murine mammary gland: a mechanism of ductal morphogenesis.
Ductal morphogenesis in the rodent mammary gland is characterized by the rapid penetration of the stromal fat pad by the highly proliferative terminal endbud and subsequent formation of an arborized pattern of ducts. The role of apoptosis in ductal morphogenesis of the murine mammary gland and its potential regulatory mechanisms was investigated in this study. Significant apoptosis was observed in the body cells of the terminal endbud during the early stage of mammary ductal development. Apoptosis occurred predominately in defined zones of the terminal endbud; 14.5% of the cells within three cell layers of the lumen were undergoing apoptosis compared to 7.9% outside this boundary. Interestingly, DNA synthesis in the terminal endbud demonstrated a reciprocal pattern; 21.1% outside three cell layers and 13.8% within. Apoptosis was very low in the highly proliferative cap cell laver and in regions of active proliferation within the terminal endbud. In comparison to other stages of murine mammary gland development, the terminal endbud possesses the highest level of programmed cell death observed to date. These data suggest that apoptosis is an important mechanism in ductal morphogenesis. In p53-deficient mice, the level of apoptosis was reduced, but did not manifest a detectable change in ductal morphology, suggesting that p53-dependent apoptosis is not primarily involved in formation of the duct. Immunohistochemical examination of the expression of the apoptotic checkpoint proteins, Bcl-x, Bax and Bcl-2, demonstrated that they are expressed in the terminal endbud. Bcl-x and Bcl-2 expression is highest in the body cells and lowest in the nonapoptotic cap cells, implying that their expression is associated with increased apoptotic potential. Bax expression was distributed throughout the terminal endbud independent of the observed pattern of apoptosis. A functional role for Bcl-2 family members in regulating endbud apoptosis was demonstrated by the significantly reduced level of apoptosis observed in WAP-Bcl-2 transgenic mice. The pattern of apoptosis and ductal structure of endbuds in these mice was also disrupted. These data demonstrate that p53-independent apoptosis may play a critical role in the early development of the mammary gland.
Animals↗
Influence of intra-osseous infusion of a small volume of hyperosmotic fluid on beta-adrenergic function in circulating lymphocytes from bled pigs.
The regulation of beta-adrenergic function in circulating mononuclear leukocytes was evaluated during an episode of haemorrhagic shock treated by intra-osseous infusion of a small volume of hyperosmotic fluid. Two groups of piglets (n = 14) were anaesthetized with ketamine and bled to a mean arterial pressure of 40 mmHg. After 45 min the animals were randomized to receive 100 ml of either hyperosmotic (2.4 mol l-1) or iso-osmotic (0.29 mol l-1) fluid (equal volumes of glucose/sodium chloride) into the tibial bone marrow. Observations of haemodynamic variables and levels of plasma catecholamines and cAMP of circulating mononuclear leukocytes were carried out for 70 min. Infusion of hyperosmotic fluid enhanced the circulatory performance and attenuated the plasma catecholamine release significantly (p < 0.05) compared to the corresponding values in the animals that had iso-osmotic fluid infusion. Measurements of unstimulated and isoprenaline-stimulated cAMP levels in mononuclear lymphocytes indicated that the high plasma catecholamine levels in the iso-osmotic treatment group induced a desensitization of the beta-adrenoceptors 70 min after initiation of the shock. This effect was not seen in animals that had undergone hyperosmotic infusion.
Animals↗
Reduced beta-adrenergic sensitivity in healthy volunteers induced by hypoglycemia.
A single causative mechanism for development of hypoglycemia unawareness in insulin-dependent diabetes mellitus (IDDM) is not yet apparent. Reduced adrenergic sensitivity may be part of the explanation. This study was carried out to investigate the effect of hypoglycemia on beta-adrenergic sensitivity. Ten healthy male subjects (age 19-23 years) gave informed consent to take part in the study. They were hospitalized overnight at the University Hospital of Tromsø, Department of Clinical Research, on two occasions. Isoprenaline and metoprolol sensitivity tests were performed the morning after hospitalization: once after an intravenous (iv) injection of placebo (0.9% NaCl), and once after an iv injection of insulin (0.15 IU insulin/kg body weight) to induce hypoglycemia. The dose of isoprenaline needed to increase heart rate (HR) by 25 beats per minute (bpm) (I25), and the dose of metoprolol (M-12.5) needed to inhibit I25 with 50% or 12.5 bpm, when injected simultaneously, were used as determinants of isoprenaline and metoprolol sensitivity. In this study, there was a significant (p < 0.05) increase both in I25 and M-12.5 after hypoglycemia. The dose-response curve of isoprenaline/HR was significantly shifted to the right after hypoglycemia. This study shows that acute hypoglycemia induces a reduction in beta-adrenergic sensitivity, and it supports the hypothesis of reduced beta-adrenergic sensitivity as an important pathophysiological mechanism in hypoglycemia unawareness in IDDM.
Adult↗
Cell density dependence of cAMP and cGMP levels in four human cell lines derived from carcinomas of the uterine cervix.
Several studies have shown altered biokinetics of cyclic nucleotides in human cancer. In order to mimic the growing tumor bulk in carcinomas of the uterine cervix, four human cell lines (C4-I, C33A, ME-180, and SiHa) were expanded in serum-supplemented cell cultures. The extra- and intracellular levels of cAMP and cGMP were determined at increasing cell densities. In all of the cell lines, a cell density-dependent increase in the extracellular cGMP/cAMP ratio was observed. cAMP was distributed to the extracellular compartment against a concentration gradient at low cell densities but was retained in the intracellular compartment at high cell densities. In contrast, cGMP was distributed to the extracellular compartment against a concentration gradient for the whole range of cell densities. This study suggests that the cell density-dependent increase in the extracellular cGMP/cAMP ratio in cell lines derived from carcinomas of the uterine cervix is a result of changes occurring in both intracellular levels and cellular excretion of cyclic nucleotides.
Cell Count↗
Renal and hepatic toxicity after high-dose 7-hydroxymethotrexate in the rat.
To examine directly the hepatic and renal toxicity of 7-hydroxymethotrexate (7-OH-MTX) without interference of the parent compound methotrexate (MTX), we purified and gave 100 mg/kg 7-OH-MTX to rats, a dose resulting in serum levels of 7-OH-MTX comparable with those achieved in the clinic after the administration of high-dose MTX (HD-MTX). After only 5 h, the 7-OH-MTX-treated rats demonstrated 2.6-fold increases in serum creatinine values and 2-fold elevations in serum aspartate aminotransferase (ASAT) levels as compared with the controls. Morphologic evidence of toxicity, however, was apparent only in the kidneys. Intraluminal cellular debris containing membranous material and deteriorated organelles was seen, but no precipitate of the delivered drug. The peak serum concentration of 7-OH was up to 939 microM, and concentrations of 7-OH-MTX declined triphasically, showing a t1/2 alpha value of 2.45 min, a t1/2 beta value of 30.5 min, and a terminal half-life (t1/2 gamma) of 240 min. The total clearance value was 14.5 ml min-1 kg, and the postdistributional volume of distribution (V beta) was 5070 ml/kg. Our results may indicate a direct toxic effect of 7-OH-MTX on kidney and liver cells.
Animals↗