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At least 91 records · Page 5Linked to original sources
PubMed1992

Spontaneous bursting and non-bursting activity in morphologically identified neurons of the rat dorsolateral septal nucleus, in vitro.

Membrane potential-dependent changes in the repetitive firing properties of morphologically identified rat dorsolateral septal nucleus neurons were investigated in a submerged slice preparation using intracellular recording techniques and lithium acetate-Lucifer Yellow-filled microelectrodes. The results indicate that the majority of dorsolateral septal nucleus neurons are capable of burst firing and suggest, moreover, the existence of neuronal subtypes with distinct differences in spike waveform and the pattern of spontaneous activity. In the largest proportion of neurons, single spike activity predominated at membrane potentials near rest while burst-like discharges prevailed at more hyperpolarized membrane potentials. Less frequently observed were neurons exhibiting different burst waveforms at various membrane potentials. In a few neurons, hyperpolarization slowed neuronal firing but did not elicit burst-like discharges. Characteristics such as the presence of burst or single spike discharges, spike afterpotentials, and the membrane potential dependence of repetitive firing patterns did not appear to be closely associated with membrane time constant, membrane resistance, or resting membrane potential. A detailed examination of the somatodendritic and axonal morphology of the Lucifer Yellow-filled cells revealed that these electrophysiologically identified neurons in the dorsolateral septal nucleus are morphologically heterogeneous. However, there did not appear to be any correlation between a particular somatodendritic morphology and the expression of a distinct spontaneous firing pattern. The present findings demonstrate that neurons in the rat dorsolateral septal nucleus are morphologically diverse and capable of intrinsically generating rhythmic neuronal activity. Similar patterns of rhythmic neuronal firing in vivo may provide a substrate for the integration of afferent neuronal activity and have a central role in intraseptal circuitry necessary for generation of hippocampal theta rhythm.

Acetates↗
PubMed1995

Different calcium channels mediate transmitter release evoked by transient or sustained depolarization at mammalian sympathetic ganglia.

We have compared the effect of calcium channel blockers on the potassium-evoked release of tritium-labeled acetylcholine and on preganglionic spike-evoked synaptic transmission in the rat superior cervical ganglion. Transmitter release at the nerve terminals is mediated by the influx of calcium through voltage-gated calcium channels. While four types of voltage-gated calcium channels (T, L, N and P) have been identified in neurons, it is not clear which may actually be involved in excitation-secretion coupling. Release of tritiated acetylcholine evoked by sustained depolarization in high (40 mM) extracellular potassium decreased markedly in the absence of calcium or the presence of cadmium. High potassium-evoked release was substantially inhibited by the P-type channel blockers, purified from funnel-web spider toxin, and omega-agatoxin-IVA, and by the N-type channel blocker omega-conotoxin-GVIA, but was unaffected by the L-type channel blocker nitrendipine. In contrast, postganglionic compound action potentials synaptically triggered by preganglionic stimulation were strongly blocked by funnel-web spider toxin and slightly blocked by a high concentration of omega-agatoxin-IVA, but were unaffected by either omega-conotoxin-GVIA, nitrendipine or a low concentration of omega-agatoxin-IVA. Thus, at the superior cervical ganglion, funnel-web spider toxin-sensitive calcium channels play a dominant role in transmitter release evoked by transient, spike-mediated depolarization, but other types of voltage-gated calcium channels in addition to the funnel-web spider toxin-sensitive channel mediate the transmitter release that is evoked by sustained high potassium depolarization.

Acetylcholine↗
PubMed1994

Early alterations in extracellular matrix and transforming growth factor beta gene expression in mouse lung indicative of late radiation fibrosis.

PURPOSE: Fibrosis, characterized by the accumulation of collagen, is a late result of thoracic irradiation. The expression of late radiation injury can be found immediately after irradiation by measuring messenger RNA (mRNA) abundance. METHODS AND MATERIALS: To determine if extracellular matrix mRNA and transforming growth factor beta abundance was affected acutely after irradiation, we measured mRNA levels of collagen I (CI), collagen III (CIII), collagen IV (CIV), fibronectin (FN), and transforming growth factor beta (TGF beta 1,2&3) in mouse lungs on day 1 and day 14 after graded doses of radiation. C57BL/6 female mice were irradiated with a single dose to the thorax of 5 or 12.5 Gy. Total lung RNA was prepared and immobilized by Northern and slot blotting and hybridized with radiolabelled cDNA probes for CI, CIII, CIV, FN, TGF beta 1,2&3 and a control probe encoding for glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Autoradiographic data were quantified by video densitometry and results normalized to GAPDH. RESULTS: Changes in the expression of CI, CIII, CIV, FN and TGF beta 1,2&3 were observed as early as 1 day after exposure. Through 14 days, changes in mRNA up to 5-fold were seen for any one dose. Dose related changes as high as 10-fold were also evident. The CI:CIII ratio increased gradually for the 5 Gy dose at 14 days postirradiation while the CI:CII ratio for the 12.5 Gy dose decreased by approximately 4-fold as compared to the control. CONCLUSION: These studies suggest that alterations in expression of extracellular matrix and TGF beta mRNA occur very early after radiation injury even at low doses and may play a role in the development of chronic fibrosis.

Animals↗
PubMed1994

Taxol and ionizing radiation: interaction and mechanisms.

PURPOSE: Taxol has been shown to be clinically active against several types of human tumors. To assess the potential oncogenic effect of taxol, the in vitro cytotoxic and oncogenic transforming effects of taxol, either alone or in combination with gamma-irradiation, were examined. METHODS AND MATERIALS: Exponentially growing mouse C3H 10T1/2 cells were treated with taxol with or without concurrent gamma-irradiation. After treatment, cultures were replated for both clonogenic survival and transformation assays. To determine the effects of taxol on cell cycle kinetics, treated cells were concurrently labelled with bromodeoxyuridine coupled with fluorescein. Accumulated mitotic cells were isolated by the shake-off technique and their plating efficiency and radiosensitivity were determined. RESULTS: Taxol induced a dose dependent toxicity in 10T1/2 cells. In contrast to human tumor cells in culture, the mitotic block induced by a 100 nM dose of taxol in 10T1/2 cells was only partial. While taxol was ineffective in transformant induction, it enhanced the oncogenic transforming potential of gamma-rays in a supra-additive manner. The fact that approximately 15% of taxol-induced mitotic cells were clonogenically viable and at a cell cycle stage that was most radiosensitive suggests a mechanistic basis for the observed enhancement in transformation incidence by ionizing radiation. CONCLUSION: Taxol enhances the oncogenicity of radiation by partially blocking the 10T1/2 cells in G2/M phases of the cell cycle, phases that are most sensitive to radiation induced oncogenic transformation.

Animals↗
PubMed1994

Misoprostol-induced radioprotection of oncogenic transformation.

PURPOSE: Prostaglandins are associated with a variety of both pathologic and normal physiological effects in mammals. Among this broad array of effects, prostaglandins have been shown to provide protection to tissues from a variety of injurious agents including ionizing radiation. Of the prostaglandins tested to date, an analogue of prostaglandin E1, misoprostol (cytotec) was found to be a very effective radioprotector. The purpose of this study was to assess the ability of misoprostol to protect cells from the cytotoxic and oncogenic effects of ionizing radiation. METHODS AND MATERIALS: Pregnant Syrian hamsters were injected subcutaneously with 125 micrograms misoprostol/100 g body weight 2 h before being exposed to graded doses of X rays. Embryos were excised immediately after irradiation and cells were explanted into culture dishes. Following 14 days of incubation, cells were fixed in formalin and stained with giemsa for examination of cell clonogenicity and morphological transformation. RESULTS: First, misoprostol protected cells from some degree of radiation toxicity. A reduction in cell killing by a factor of 1.5 was seen at 10% cell survival. Second, based on transformation studies, a higher frequency of oncogenic transformation is seen for cells exposed in utero to graded doses of X rays alone than for cells exposed to the combination of misoprostol followed by radiation. In the presence of misoprostol, transformation is reduced by a factor of 20 at the level of 10(-3) transformants per surviving cell. CONCLUSION: Misoprostol may have clinical utility, not only in protecting selected normal tissues during cancer therapy, but it may also be useful in protecting cells from secondary tumors caused by ionizing radiation.

Animals↗
PubMed1995

Photoneutrons from medical linear accelerators--radiobiological measurements and risk estimates.

PURPOSE: To assess the oncogenic potential of the photoneutrons produced by high energy medical linear accelerators. METHODS AND MATERIALS: An established line of cells of rodent origin (C3H 10T1/2) was used to assess the oncogenic potential of the radiation dose received in the breast of an anthropomorphic "randoman" phanton, while the cervix received a dose of 70 Gy. Experiments were performed at 6 MV, below the threshold for the production of photoneutrons, and at 20 MV where the dose includes about 0.01 Gy of photoneutrons as well as scattered x-rays. RESULTS: A significantly higher transformation incidence was observed for the 20-MV machine, consistent with the measured neutron dose of about 0.01 Gy and a quality factor of 20. CONCLUSION: An estimate can be made of the additional deaths from second malignancies that might result from the photoneutrons generated by higher energy linear accelerators (Linacs), which must be offset against the possible improvements in survival that might result from the higher tumor doses made possible by the increased percentage depth doses.

Animals↗
PubMed1995

A convenient extension of the linear-quadratic model to include redistribution and reoxygenation.

PURPOSE: At present, the linear-quadratic model for cellular response to radiation can incorporate sublethal damage repair and repopulation. We suggest an extension, termed LQR, to include also the other two "Rs" of radiobiology, cell cycle redistribution, and reoxygenation. METHODS AND MATERIALS: In this approach, redistribution and reoxygenation are both regarded as aspects of a single phenomenon, which we term resensitization. After the first portion of a radiation exposure has decreased the average radiosensitivity of a diverse cell population by preferentially sparing less sensitive cells, resensitization gradually restores the average sensitivity of the population towards its previous value. The proposed LQR formula is of the same form as the original LQ formula, but with two extra parameters, an overall resensitization magnitude and a characteristic resensitization time. The LQR model assumes that resensitization is monotonic rather than oscillatory in time, i.e., always tends to increase average cellular sensitivity as overall time increases. We argue that this monotonicity assumption is likely to hold in clinical situations, though a possible extension is discussed to account for oscillatory decay of resensitization effects. RESULTS: The LQR model gives reasonable fits to relevant experimental data in the literature, reproducing an initial rise in cell survival, due to repair, as the treatment time is increased, followed by a resensitization-related decrease in survival due to redistribution and/or reoxygenation for treatment times of the order of the cell cycle time, and a final survival increase due to repopulation as the treatment time is increased still further. CONCLUSION: The LQR model is a simple and potentially useful extension of the LQ model for computing more realistic isoeffect relations for early responding tissues, including tumors, when comparing different radiotherapeutic protocols.

Animals↗
PubMed1991

The mechanical control system of bone in weightless spaceflight and in aging.

Bone loss is notable in elderly persons and in astronauts returning from spaceflight, however, the bone changes in these radically different patient populations appear morphologically similar. Bone structure depends upon several independent basic processes: growth, modeling, and remodeling. Each process follows a stereotyped sequence of steps. Alteration of any step may yield a similar bone loss, although from an entirely different mechanism. Mechanical forces appear to coordinate the fundamental bone shaping processes by a negative feedback control system. Determining how mechanical signals control the mass, architecture, and strength of bone may establish the limits by which exercise can prevent osteoporosis in the elderly and in astronauts despite obvious differences in etiology.

Adult↗
PubMed1989

Left subclavian flap aortoplasty for coarctation of the aorta: effects on forearm vascular function and growth.

This study evaluated vascular function and growth of the forearm in nine children (mean age 9.2 years) who had undergone left subclavian flap aortoplasty for the infantile type of coarctation of the aorta many years (mean 9.0) earlier. Variables used to investigate bilateral forearm vascular function included forearm blood flow and resistance measured by strain gauge plethysmography under rest conditions, in response to 30 s of static handgrip exercise at 40% maximal voluntary contraction and in response to 10 min of forearm arterial occlusion (that is, the reactive hyperemic blood flow response). Forearm growth was ascertained by measuring right and left forearm volumes, lengths, circumferences and skinfold thickness. Mean arterial pressure at rest in the right and left arms differed by 9% (right 78.2 +/- 2.1, left 71.0 +/- 2.7 mm Hg; p less than 0.05). Forearm blood flow, however, was not significantly different between the surgically altered left arm and the normal right arm under any of the study conditions. Likewise, forearm vascular resistance was not statistically different under any conditions, although the left arm tended to have a lower resistance at rest (right 23.5 +/- 3.2, left 18.7 +/- 2.0 mm Hg.min.100 ml/ml; p = 0.057). Left forearm anthropometric measurements showed a 9% reduction in volume and a 3% reduction in circumference and length. In addition, skinfold thickness tended to be larger on the left arm, suggesting that this limb had a smaller muscle mass. In conclusion, early repair with a subclavian flap does not impair vascular function in the altered limb and is associated with only minor reductions in forearm growth variables. Hence, left subclavian flap aortoplasty appears to be a safe and effective procedure for repair of coarctation of the aorta.

Aortic Coarctation↗
PubMedDate not supplied

Effect of a metallothionein antisense oligonucleotide on embryo development.

The effect of a metallothionein (MT) antisense oligodeoxynucleotide (ODN) on mouse preimplantation embryo development was investigated. Preimplantation embryos were cultured for 72 h and examined following exposure to either an MT antisense or sense ODN. Blastocyst formation (cavitation) and embryo cell number were lower in embryos exposed to the MT antisense ODN than in controls or in embryos exposed to the MT sense ODN. In embryos cultured in medium containing free nucleotides, cavitation frequency was not affected, although mean embryo cell number was lower than in controls. Combined, this work shows that an antisense ODN against MT can significantly affect blastocyst formation of preimplantation embryos; some, but not all, of the observed effects on embryo cell number may have been due to nucleotide toxicity.

Analysis of Variance↗
PubMed1993

Shear sensitivity in animal cell culture.

Over the past year, considerable progress has been made in understanding shear sensitivity in animal cell culture as a result of extensive theoretical and experimental work. Here we review this progress, paying special attention to the physical and biological mechanisms by which mechanical forces act upon cells, and the effects of such forces.

Animals↗
PubMed1994

In vitro genetic analysis of the hinge region between helical elements P5-P4-P6 and P7-P3-P8 in the sunY group I self-splicing intron.

Modeling of the group I intron RNA suggests that its catalytic core is primarily composed of two extended structural elements (stacked helices P5-P4-P6 and P7-P3-P8) whose relative orientation is partially determined by base-triple interactions between paired regions P4 and P6, and single-stranded joining regions J6/7 and J3/4, respectively. In vitro genetic selection was used to isolate functional sequence variants of the proposed triple helical domain of the sunY intron. Comparative sequence analysis of the selected variants provided supporting evidence for the two previously established base-triples between P4 and J6/7 and provided the first experimental evidence for an interaction between P6(1) and J3/4(3). Sequence covariations also indicated that a simple relationship exists between the length of a single-stranded joining region, J3/4, and the identity of a particular base-pair, P4(1). Selected variants based on a core structure with an extra nucleotide inserted in J3/4 revealed two different responses to this structural perturbation: a base-triple interaction and an intrahelical bulged pyrimidine. Chemical modification analysis supported the existence of these alternative structures. The function of this region of the ribozyme can therefore be fulfilled by at least three different structures.

Animals↗
PubMed1993

Assay of vesicle motility in squid axoplasm.

Axoplasm prepared as described above will maintain high levels of fast axonal transport for 1-2 hours, although moderate decrements in the average velocity may be noted over time. The organelles and structures that can be detected in isolated axoplasma are as small as the 50-nm synaptic vesicles or 25-nm microtubules, well below the limits of resolution for light microscopy; however, in the center of the axoplasm, where the density of structures is high, individual microtubules are not readily distinguished and individual vesicles can be followed only for short distances before they move out of the plane of focus or are lost in the multitude of neighboring organelles. On the periphery of perfused axoplasm, each of these structures may be readily detected and analyzed, but some information is lost about the role of specific axoplasmic organization in normal transport processes. Fortunately, the juxtaposition in one preparation of essentially structurally intact axoplasm with the extracted individual microtubules transporting organelles provides a unique preparation for molecular dissection of intracellular transport (Brady et al., 1985).

Animals↗
PubMed1995

Delayed neuropsychologic sequelae after carbon monoxide poisoning: prevention by treatment with hyperbaric oxygen.

STUDY OBJECTIVE: Carbon monoxide (CO) poisoning is a major clinical problem. The risk of morbidity and the most effective treatment have not been clearly established. We measured the incidence of delayed neurologic sequelae (DNS) in a group of patients acutely poisoned with CO and tested the null hypothesis that the incidence would not be affected by treatment with hyperbaric oxygen (HBO). DESIGN: We conducted a prospective, randomized study in patients with mild to moderate CO poisoning who presented within 6 hours. Patients had no history of loss of consciousness or cardiac instability. INTERVENTIONS: The incidence of DNS was compared between groups treated with ambient pressure 100% oxygen or HBO (2.8 ATA for 30 minutes followed by 2.0 ATA oxygen for 90 minutes). DNS were defined as development of new symptoms after oxygen treatment plus deterioration on one or more subtests of a standardized neuropsychologic screening battery. RESULTS: In 7 of 30 patients (23%), DNS developed after treatment with ambient-pressure oxygen, whereas no sequelae developed in 30 patients after HBO treatment (P < .05). DNS occurred 6 +/- 1 (mean +/- SE) days after poisoning and persisted 41 +/- 8 days. At follow-up 4 weeks after poisoning, patients who had been treated with ambient pressure oxygen and had not sustained DNS exhibited a worse mean score on one subtest, Trail Making, compared with the group treated with HBO and with a control group matched according to age and education level. There were no differences in scores between the control group and the hyperbaric oxygen group. CONCLUSION: DNS after CO poisoning cannot be predicted on the basis of a patient's clinical history or CO level. HBO treatment decreased the incidence of DNS after CO poisoning.

Adolescent↗
PubMed1983

Long-term therapy with a new cardiotonic agent, WIN 47203: drug-dependent improvement in cardiac performance and progression of the underlying disease.

Seven patients with severe chronic congestive heart failure were treated with a new cardiotonic agent, WIN 47203 (an analog of amrinone), for an average of 7.4 weeks (range 2 to 15). At the initiation of therapy, hemodynamic improvement occurred in all patients as the cardiac index increased from 1.79 +/- 0.39 to 2.30 +/- 0.44 liters/min per m2 (probability [p] less than 0.05) and pulmonary capillary wedge pressure decreased from 24.1 +/- 6.7 to 16.1 +/- 7.8 mm Hg (p less than 0.05). Long-term therapy produced a substantial symptomatic improvement in five of the seven patients. This improvement was fully sustained in two patients and the remaining three experienced a partial return of their symptoms even though the initial hemodynamic improvements at rest remained evident in all seven patients. Withdrawal of WIN 47203 precipitated hemodynamic deterioration in all patients. The cardiac index decreased from 2.25 +/- 0.40 to 1.64 +/- 0.46 liters/min per m2 (p less than 0.05) while the pulmonary capillary wedge pressure increased from 17.1 +/- 7.8 to 23.2 +/- 12.0 mm Hg (p less than 0.05). Stroke volume index after withdrawal was lower than the control level before therapy (17.0 +/- 6.6 versus 20.3 +/- 4.7 ml/m2; p less than 0.05) and pulmonary capillary wedge pressure was similar. During long-term therapy, no undesirable side effects or hematologic changes were observed. Thus, drug-dependent hemodynamic benefits and apparent progression of the underlying cardiac disease were demonstrated during long-term therapy with WIN 47203.

Cardiac Output↗
PubMed1994

Molecular determinants of recognition and activation at the cerebellar benzodiazepine receptor site.

Semiempirical quantum mechanical and molecular mechanics calculations were carried out to identify and characterize the steric and electronic properties that modulate ligand recognition and activation of the cerebellar GABAA/benzodiazepine (BDZ) receptor. For this hypothesis development, thirteen compounds belonging to structurally diverse chemical families were selected for study. Among the compounds selected were nine that bind and four that do not bind with appreciable affinity to this receptor and some that are known agonists, antagonists and inverse agonists, as measured by their modulation of GABA (gamma-aminobutyric acid) enhanced chloride ion flux in cerebellum. The stereoelectronic requirements for recognition deduced from commonalities among the ligands are the presence of at least two of three hydrogen bonding centers, and a lipophilic aromatic ring, in a specific spatial relationship. The results suggest that the selectivity for the cerebellar or Type I subtype, demonstrated by some of these ligands, could be failure to meet the requirements for binding at other receptors because of the absence of one of the proton accepting centers or the larger surface area and volume of these ligands. The requirement for activation, deduced from comparisons of agonist, antagonist, and inverse agonist properties is the presence of an electron accepting aromatic ring in a specific geometric arrangement with respect to the components of recognition. The validity of the '3D-Pharmacophore' developed was probed by using it for predictions of the behavior of 11 additional compounds not used for its development.

Animals↗
PubMed1994

In vitro selection of RNA aptamers specific for cyanocobalamin.

RNA receptors (aptamers) capable of specifically binding cyanocobalamin (vitamin B12) have been isolated by in vitro selection from a pool of 5 x 10(14) RNAs of random sequence. After eight rounds of selection by affinity chromatography and enzymatic amplification, the pool was dominated by two sequences. The major sequence, comprising 60% of the pool, was studied further. It was found to bind vitamin B12 in solution with a dissociation constant (Kd) of approximately 320 +/- 90 nM and to bind cobinamide dicyanide with a Kd of 8.8 +/- 0.5 microM. The aptamer does not detectably bind adenosylcobalamin (coenzyme B12). The selection was conducted in 1 M LiCl, and binding is dependent on the presence of high concentrations of Li+ but independent of Mg2+. To define the binding site for cyanocobalamin, a second cyanocobalamin-binding selection was carried out using a pool of sequences derived from the major aptamer sequence randomized at a level of 30%. The sequence data from this selection revealed a 31-base highly conserved region, on the basis of which was synthesized a smaller aptamer of 35 nucleotides. This small aptamer binds cyanocobalamin in solution with a Kd of 88 +/- 19 nM and cobinamide dicyanide with a Kd of 20 +/- 9 microM. This aptamer has the highest affinity yet reported for a small molecule ligand. A number of covarying positions were found in the conserved region of the sequences from this second, mutagenized pool selection. On the basis of these data, an unusual pseudoknot secondary structure is proposed for the aptamer. Chemical modification protection experiments are consistent with this structure and have demonstrated that the RNA undergoes a conformational change upon binding its ligand. Possible contacts with the cyanocobalamin have also been mapped. A third selection was carried out in which the salt specificity of the aptamer was changed from LiCl to NaCl plus MgCl2. Sequence analysis of the final round pool of RNAs from this selection revealed several conserved changes from the original vitamin B12 aptamer sequence.

Base Sequence↗