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Biomedical subjects

M Williams

Publications and source records attributed to M Williams.

At least 541 records · Page 30Linked to original sources
PubMed1988

High colony-forming efficiency of primary human tumor cells cultured in the adhesive-tumor-cell culture system: improvements with medium and serum alterations.

The colony-forming efficiency (CFE) of primary human tumor cells cultured in the adhesive-tumor-cell culture system (ATCCS) using Ham's F12 (F12) or Eagle's minimum essential medium, alpha modification (alphaMEM) and culture medium supplemented with either swine, equine or bovine sera were compared. AlphaMEM supplemented with equine serum provided the highest CFE of the combinations. The CFE increase due to the change from F12 to alphaMEM was approximately 5-fold, and the increase due to the change in serum from swine to equine was approximately 2-fold. Cytokeratin staining showed that this increase was not due to fibroblast growth. The high-average CFE with alphaMEM, approximately 3%, means that an inoculum of only 2 X 10(3) cells is needed to achieve formation of approximately 65 colonies in control cultures, thereby increasing the performance of this system when used in a chemosensitivity assay.

Cell Adhesion↗
PubMed1988

The novel N-methyl-D-aspartate (NMDA) antagonist CGS 19755 prevents ischemia-induced reductions of adenosine A1, NMDA, and PCP receptors in gerbil brain.

Transient brain ischemia results in a selective destruction of cell bodies within the hippocampus and cortex. This cellular destruction appears to be mediated through a release of endogenous exictatory amino acids following the ischemic episode, since the neurotoxic effects of ischemia can be attenuated by compounds that have antagonist activity at N-methyl-D-aspartate (NMDA) receptors. In the present study, the protective effects of a novel NMDA receptor antagonist, CGS 19755, were further evaluated by using quantitative autoradiography to characterize adenosine A1, NMDA, PCP, and benzodiazepine receptors in ischemic gerbil brain. Bilateral carotid artery occlusion (20 minutes) resulted in marked decreases (30-60%) in adenosine A1, NMDA, and PCP, but not benzodiazepine, receptors in gerbil forebrain. Postischemic treatment with CGS 19755 was found to completely block the ischemia-induced decreases in brain adenosine and NMDA receptors. [3H]TCP binding in ischemic gerbil brain was also elevated by CGS 19755 treatment; significant differences remained, however, between the CGS 19755-treated and control gerbils. These results indicate that transient brain ischemia produces significant and selective alterations in gerbil forebrain receptor systems. The observed decreases in radioligand binding are probably reflective of an ischemia-induced destruction of forebrain structures. However, there is some evidence that transient ischemia can also cause long-term changes in the affinity of some receptor systems. The postischemic efficacy of CGS 19755 appears to be due to its ability to block the neurotoxic effects of transient ischemia.

Adenosine↗
PubMed1988

Interactions of isamoltane (CGP 361A), an anxiolytic phenoxypropanolamine derivative, with 5-HT1 receptor subtypes in the rat brain.

Isamoltane (CGP 361A; (1-(2-(1-pyrrolyl)-phenoxy)-3-isopropylamino-2-propanol hydrochloride), a beta-adrenoceptor ligand (IC50 = 8.4 nmol/l) which has reported activity as an anxiolytic in man was found to be a reasonably active inhibitor of the binding of [125I]ICYP to 5-HT1B recognition sites in rat brain membranes with 27-fold selectivity (IC50 = 39 nmol/l) as compared to the inhibition of binding of [3H]8-OH-DPAT to 5-HT1A receptors (IC50 = 1070 nmol/l). This selectivity was considerably greater than that observed for other beta-adrenoceptor ligands including propranolol (5-HT1A/5-HT1B ratio = 2), oxpenolol (3.5) and cyanopindolol (8.7). The 5-HT1B activity of the compound resided in the (-)-enantiomer. (-)-Isamoltane had weak activity (IC50 3-10 mumol/l) at 5-HT2 and alpha 1-adrenoceptors. The compound was devoid of activity at a number of other central neurotransmitter recognition sites including the 5-HT1C site. Isamoltane increased the electrically evoked release of [3H]5-HT from prelabeled rat cortical slices in a manner similar to that of cyanopindolol. While both compounds were similar in potency to methiothepin, they had lower efficacy. Oxprenolol was less potent that both isamoltane and cyanopindolol while propranolol was essentially inactive. The effects of the compounds on 5-HT release appeared to be correlated with their 5-HT1B rather than 5-HT1A activity. In vivo, isamoltane increased 5-HTP accumulation in rat cortex following central decarboxylase inhibition at doses of 1 and 3 mg/kg i.p. At higher doses this effect was gradually diminished. Similar, but less clearcut results were obtained with cyanopindolol and oxprenolol, but propranolol was ineffective. No changes in brain tryptophan levels were associated with the isamoltane-evoked changes in brain 5-HTP levels. In reserpinized animals, isamoltane reduced 5-HTP accumulation even at doses which enhanced accumulation of this metabolite when given alone. The effects of the putative 5-HT1B agonist, m-trifluoromethylphenylpiperazine (TFMPP), the mixed 5-HT autoreceptor agonist/antagonist/beta-adrenoceptor antagonist, pindolol, the 5-HT uptake inhibitor, CGP 6085A and the MAO-A inhibitor, brofaromine, were not antagonized by pretreatment with isamoltane. The possibility that isamoltane and the other beta-adrenoceptor antagonists are antagonists at 5-HT1B receptors and that their effect on 5-HT synthesis in vivo is the net result of their agonist/antagonist effects at 5-HT1A and 5-HT1B receptors is discussed in relation to the potential mechanism of the anxiolytic activity of isamoltane.

5-Hydroxytryptophan↗
PubMed1988

Differences in adenosine A-1 and A-2 receptor density revealed by autoradiography in methylxanthine-sensitive and insensitive mice.

Two strains of inbred mice, CBA/J and SWR/J, have been identified which are, respectively, sensitive and insensitive to the behavioral and toxic effects of methylxanthines. Autoradiographic analyses of brain adenosine receptors were conducted with [3H]CHA to label adenosine A-1 receptors and [3H]NECA, in the presence of 50 nM CPA, to label adenosine A-2 receptors. For both mouse strains, adenosine A-1 receptors were most highly concentrated in the hippocampus and cerebellum whereas adenosine A-2 receptors were selectively localized in the striatum. CBA/J mice displayed a 30% greater density of adenosine A-1 receptors in the hippocampal CA-1 and CA-3 regions and in the cerebellum as compared to the SWR/J mice. The number of A-2 receptors (Bmax) was 40% greater in the striatum and olfactory tubercle of CBA/J as compared to SWR/J mice. No significant regional differences in A-1 or A-2 receptor affinities were observed between these inbred strains of mice. These results indicate that the differential sensitivity to methylxanthines between these mouse strains may reflect a genetically mediated difference in regional adenosine receptor densities.

Adenosine↗
PubMed1988

Adenosine antagonists as potential therapeutic agents.

The methylxanthine caffeine has been identified in more than 60 plant species and has been in human use for its various therapeutic actions for many hundreds of years and perhaps, with the exception of aspirin and related compounds, is the most widely consumed drug today. Pharmacologically, the xanthines are prototypic inhibitors of the enzyme, cyclic nucleotide phosphodiesterase, are calcium mobilizers and have been reported to inhibit the enzymes, monoamine oxidase and cyclooxygenase as well as affect uptake of the putative neuromodulator, adenosine. However, many of the therapeutic effects ascribed to caffeine are due to its selective ability to antagonize the actions of adenosine. Many xanthines, especially those substituted in the 8-position with a phenyl derivative, are potent and selective adenosine antagonists. The xanthine adenosine antagonists have mild psychostimulant, analgesic adjuvant, diuretic, cardiotonic and antiasthmatic activity. Adenosine antagonists also have nootropic activity. A major limiting factor to the development of this class of compound has been in the lack of selectivity for either of the major classes of adenosine receptor. Several non-xanthines including the pyrazolopyrimidine, DJB-KK, the pyrazoloquinoline, CGS 8216 and the pyrazolopyridine, etazolate have been shown to have adenosine antagonist activity. The triazoloquinazoline, CGS 15943 A has been identified as the first, potent (IC50 = 3 nM) nonxanthine, A2-selective adenosine antagonist while the phenylquinazoline, HTQZ, has 25-fold selectivity for the A2 receptor. The availability of such novel entities may permit the development of a new class of therapeutic agents able to affect neuromodulator, as opposed to neurotransmitter, function.

Adenosine↗
PubMed1988

Thalamic pain--the effect of electroconvulsive therapy (ECT).

An open study of the effect of a standard course of unilateral ECT applied to 4 patients with intractable thalamic pain. There was no significant change in pain, personality or affective profiles after treatment. Venous plasma endorphins were measured during the ECT course and there were no significant correlations with treatment.

Aged↗
PubMed1988

A comparison of survival, growth, and pulmonary function in patients with cystic fibrosis in Boston and Toronto.

Two cystic fibrosis (CF) clinic populations of similar size and age distribution were compared with respect to growth, pulmonary function, and survival. Height and weight measurements were made on 499 patients in Boston (mean +/- SD age 15.9 +/- 9.6, range 1 month to 45 years) and on 534 patients in Toronto (mean +/- SD age 15.2 +/- 8.3, range 1 month to 43 years). Males constituted 57% in the Boston group, 58% in Toronto. Pulmonary function test results were recorded for 64% of the Boston patients and 77% of the Toronto patients. Survival curves for the period 1972-1981 generated by the CF Patient Registry were compared. Patients in Boston tended to be shorter than patients in Toronto. This pattern was seen in both sexes in the 10-20 year age groups. Toronto males also weighed more than Boston males. Mean forced expiratory volume in one second (FEV1) was not different in Boston and Toronto CF patients whether expressed as a percent of predicted or in litres by age groups. Median age of survival in Boston was 21 years, in Toronto 30, the two curves showing a marked separation from age 10. Although progressive pulmonary disease is the major cause of mortality in cystic fibrosis, the differences in growth and survival in these two patient groups, with very similar age-specific pulmonary function, suggest further examination of nutritional guidance and intervention in CF, especially regarding the traditional restriction of dietary fat.

Adolescent↗
PubMed1988

Characterization of the binding of [3H]-CGS 19755: a novel N-methyl-D-aspartate antagonist with nanomolar affinity in rat brain.

1. CGS 19755 (cis-4-phosphonomethyl-2-piperidine carboxylic acid), a rigid analogue of 2-amino-5-phosphonopentanoic acid (AP5), is one of the most potent competitive N-methyl-D-aspartate (NMDA) antagonists described. Using Triton-treated crude synaptic membranes from rat brain, binding studies indicated that [3H]-CGS 19755 bound with high affinity and selectivity to the NMDA-type excitatory amino acid receptor. 2. [3H]-CGS 19755 binding was saturable, reversible, heat-labile, pH-dependent and linear with protein concentration. Specific binding represented 80-85% of the total amount bound. 3. Using a centrifugation assay, saturation experiments revealed two distinct binding components with Kd values of 9 and 200 nM, and corresponding Bmax values of 0.55 and 1.00 pmol mg-1 protein. In contrast, a single binding component with a Kd value of 24 nM and an apparent Bmax value of 0.74 pmol mg-1 protein was observed with a filtration assay. 4. Competition experiments in which both assay techniques were used, showed that [3H]-CGS 19755 selectively labels the NMDA receptor. The most active inhibitors of [3H]-CGS 19755 binding were L-glutamate and CGS 19755 (IC50 values = 100 nM). 5. In the centrifugation assay, a number of excitatory amino acids were found to generate shallow inhibition curves, and computer analysis indicated the presence of two binding components. The quisqualate receptor ligand AMPA (D,L-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate), kainic acid and the non-competitive NMDA antagonists, such as phencyclidine, tiletamine and MK-801, were without activity. 6. The high affinity binding obtained with [3H]-CGS 19755 by use of filtration techniques thus permits the more rapid evaluation of compounds as potential NMDA antagonists and agonists. Therefore, this rigid analogue of AP5 is a more suitable radioligand for NMDA receptors than [3H]-CPP (34-+/-)2-carboxypiperazin-4-yl)propyl-1-phosphonic acid), the corresponding analogue of 2-amino-7-phosphonoheptanoic acid (AP7).

Animals↗
PubMed1988

The contribution of the excitatory source to the perception of neutral vowels in stuttered speech.

The vowel in part-word repetitions in stuttered speech often sounds neutralized. In the present article, measurements of the excitatory source made during such episodes of dysfluency are reported. These measurements show that, compared with fluent utterances, the glottal volume velocities are lower in amplitude and shorter in duration and that the energy occurs more towards the low-frequency end of the spectrum. In a first perceptual experiment, the effects of varying the amplitude and duration of the glottal source were assessed. The glottal volume velocity recordings of the /ae/ vowels used in the analyses were employed as driving sources for an articulatory synthesizer so that judgments about the vowel quality could be made. With dysfluent glottal sources (either as spoken or by editing a fluent source so that it was low in amplitude and brief), the vowels sounded more neutralized than with fluent glottal sources (as spoken or by editing a dysfluent source to increase its amplitude and lengthen it). In a second perceptual experiment, synthetic glottal volume velocities were used to verify these findings and to assess the influence of the low-frequency emphasis in the dysfluent speech. This experiment showed that spectral bias and duration both cause stuttered vowels to sound neutralized.

Adult↗
PubMed1988

Total parenteral nutrition by intraperitoneal feeding in rabbits.

The possibility of intraperitoneal (IP) parenteral nutrition was suggested after the observation that glucose and amino acids pass from the peritoneal cavity into the systemic circulation. We used rabbits to study the characteristics of the transfer of glucose, lipids and amino acids. An IP injection of glucose 25% (1 g/kg) produced a peak level in the serum within 40 min. A 20% fat solution (1 g/kg) showed maximum serum levels of triglycerides and total lipid in 2.5 h, while a standard amino acid solution (1.5 g/kg) enriched with 25 14C-phenylalanine peaked serum levels in 16 min. The 4 rabbits survived for 28 days with IP glucose, amino acids and lipids as the only form of nutrition, apart from water. When sacrificed after 28 days histology of peritoneum, liver, spleen, gut and kidney showed no abnormality. We conclude that the basic nutritional components are adequately absorbed through the peritoneum, and that long-term nutritional support can be achieved uneventfully with IP administration of nutritional solutions.

Absorption↗
PubMed1988

Assessment of sound in the ear canal caused by movement of the jaw relative to the skull.

To assess whether or not the reduction of threshold to bone-conducted sound on occlusion of the ears (the occlusion effect) is due to compression of the auditory meatus by the jaw, measurements of movement of the skull and mandible and sound in the ear canal are reported from four subjects. The change in bone-conducted sound in the ear canal was also measured when the mandible was moved out and in (presenting more or less of the mandible to compress the auditory meatus) and when vibration was applied directly to the mandible. Sound pressure increased when the jaw was moved out and when vibration was applied to the mandible.

Air Pressure↗
PubMed1988

Interaction of the D1 receptor antagonist SCH 23390 with the central 5-HT system: radioligand binding studies, measurements of biochemical parameters and effects on L-5-HTP syndrome.

The interaction of SCH 23390 with dopamine (DA) and serotonin (5-HT) systems has been examined in vivo and in vitro. Like selective 5-HT2 blockers, SCH 23390 inhibited in vivo [3H]spiperone binding in the rat frontal cortex (ID50: 1.5 mg/kg) without interacting at D2 sites. SCH 23390 was equipotent to cinanserin and methysergide. In vitro, SCH 23390 inhibited [3H]ketanserin binding to 5-HT2 sites (IC50 = 30 nM). Biochemical parameters linked to DA and 5-HT were not changed excepted in striatum where SCH 23390 increased HVA and DOPAC. In the L-5-HTP syndrome model, SCH 23390 clearly showed antagonism of 5-HT2 receptors. SCH 23390 had weak affinity for 5-HT1B (IC50 = 0.5 microM), 5-HT1A (IC50 = 2.6 microM) and alpha 1-adrenergic receptors (IC50 = 4.4 microM).

5-Hydroxytryptophan↗
PubMed1988

The N-methyl-D-aspartate receptor complex.

The effects of agonists of the N-methyl-D-aspartate (NMDA) receptor can be blocked by dissociative anesthetics such as phencyclidine (PCP) in a non-competitive manner. This finding together with the fact that ligand binding to the PCP receptor is dependent on the presence of L-glutamate has led to the suggestion that there may exist an NMDA/PCP receptor complex in mammalian brain tissue. This concept has been extended to the inclusion of a cation channel based on the inhibitory actions of the divalent cation, magnesium. Evaluation of the binding of tritiated TCP (thienylcyclohexylpiperidine) a high affinity ligand for the PCP receptor, under four conditions: in basal, well washed rat cortical membranes; in the presence of L-glutamate; in the presence of magnesium; and in the presence of both magnesium and L-glutamate, with NMDA antagonists and dissociative anesthetics showed that these agents had distinct profiles of activity at the PCP receptor. Furthermore, while both classes of compound could modulate TCP binding, only NMDA receptor antagonists inhibited the binding of tritiated CPP (3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid) which labels central NMDA recognition sites. The present data support the existence of an NMDA/PCP receptor complex in mammalian brain tissue. The data currently available would suggest however, that the interface is sequentially NMDA to PCP with the latter site affecting NMDA-mediated responses at a step intermediate between receptor activation and physiological response.

Anesthetics, Dissociative↗
PubMed1988

Antibodies to Epstein-Barr virus-specific DNase and DNA polymerase in the chronic fatigue syndrome.

In an attempt to examine further the association between active Epstein-Barr virus (EBV) infection and the chronic fatigue syndrome (chronic EBV syndrome, or chronic or atypical mononucleosis), antibodies acting against EBV-specific DNase and DNA polymerase, which are expressed only during virus replication, were assayed. Serum samples from 25 healthy EBV-seropositive individuals neutralized 3.5 +/- 5.1 U (mean +/- SD) of DNase activity and 14.7 +/- 8.5 U of DNA polymerase activity. From these values were selected upper limits of anti-EBV enzyme activity of 17.9 and 31.3 U neutralized in normal individuals, respectively (representing the 95% confidence limit). Serum samples from six groups of subjects representing a variety of EBV-related illnesses were then studied. Only patients with notably elevated anti-EBV antibody titers to viral capsid antigen (VCA) (greater than 10,000) had elevated levels of anti-EBV DNase (38 to 56 U neutralized) and anti-EBV DNA polymerase (72 to 106 U neutralized). Three additional patients and two geriatric controls with average anti-EBV early antigen/VCA titers had slightly elevated levels of antibody to EBV DNA polymerase. IgA anti-VCA, anti-early antigen antibodies, or both, were also detected in the same patients who had high EBV DNase and polymerase antibody levels. These antibody profiles are similar to those in patients with nasopharyngeal carcinoma. Since three of the six patients with elevated anti-EBV enzyme antibody levels developed fatal lymphomas, patients with chronic EBV and this antibody profile might be in another illness category at risk for malignant disease.

Aged↗
PubMed1988

Correlation between binding affinities for brain A1 and A2 receptors of adenosine agonists and antagonists and their effects on heart rate and coronary vascular tone.

The activities of a series of A1 and A2 adenosine receptor agonists and antagonists were determined using radioligand binding techniques in rat brain tissues. The potencies of these agonists on heart rate and coronary vascular tone were also assessed in the perfused working rat heart preparation. The order of potency of these agonists in producing negative chronotropic effects was similar to the rank order for their A1 receptor binding activities [6-N-cyclohexyladenosine (CHA) = 6-N-(R-phenylisopropyl)-adenosine greater than 5'-N-ethylcarboxamideadenosine (NECA) = 2-chloroadenosine greater than 2-phenylaminoadenosine] with a correlation coefficient of 0.97. Their order of potency in reducing coronary vascular tone followed the same rank order as their A2 receptor binding activities with a correlation coefficient of 0.97 (NECA greater than 2-chloroadenosine = 6-N-(R-phenylisopropyl)-adenosine = 2-phenylaminoadenosine greater than CHA). In addition, the antagonists 8-[4-[[[[(2-aminoethyl)amino]carbonyl]methyl]ox]phenyl-1,3- dipropylxanthine (XAC), 1,3-dipropyl-8-(2-amino-4-chlorophenyl) xanthine (PACPX) and 8-phenyltheophylline (8-PT) blocked the negative chronotropic effect of CHA and the vasodilatory effect of NECA in a concentration-dependent manner. The same order of potency of the antagonists was noted in blocking CHA-induced bradycardia and A1 receptor binding activities (XAC = PACPX greater than 8-PT). A similar correlation was observed for their effects in blocking NECA-induced vasodilation and A2 receptor binding activity (XAC greater than PACPX greater than 8-PT).(ABSTRACT TRUNCATED AT 250 WORDS)

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1988

CGS 19755, a selective and competitive N-methyl-D-aspartate-type excitatory amino acid receptor antagonist.

CGS 19755 (cis-4-phosphonomethyl-2-piperidine carboxylic acid) was found to be a potent, stereospecific inhibitor of N-methyl-D-aspartate (NMDA)-evoked, but not KCl-evoked, [3H] acetylcholine release from slices of the rat striatum. The concentration-response curve to NMDA was shifted to the right by CGS 19755 (pA2 = 5.94), suggesting a competitive interaction with NMDA-type receptors. CGS 19755 inhibited the binding of [3H]-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid to NMDA-type receptors with an IC50 of 50 nM, making it the most potent NMDA-type receptor antagonist reported to date. CGS 19755 failed to interact with 23 other receptor types as assessed by receptor binding, including the quisqualate- and kainate-type excitatory amino acid receptors. In crude P2 fractions, no evidence was obtained to suggest that CGS 19755 is taken up by an active transport system. Furthermore, CGS 19755 failed to affect the uptake of L-[3H]glutamate, or to interact with aconitine-induced inhibition of L-[3H]glutamate uptake, the latter finding suggesting a lack of membrane-stabilizing or local anesthetic properties. CGS 19755 selectively antagonized the excitatory effect of iontophoretically applied NMDA in the red nucleus of the rat without affecting the excitatory effects of quisqualate. CGS 19755 blocked the harmaline-induced increase in cerebellar cyclic GMP levels at a dose of 4 mg/kg i.p. with a duration of action exceeding 2 hr. CGS 19755 inhibited convulsions elicited by maximal electroshock in rat (ED50 = 3.8 mg/kg i.p. 1 hr after administration) and in mouse (ED50 = 2.0 mg/kg i.p. 0.5 hr after administration). Likewise, convulsions elicited by picrotoxin were inhibited by CGS 19755, whereas the compound was relatively weak in protecting against convulsions elicited by pentylenetetrazole or strychnine. CGS 19755 produced retention performance deficits in a dark avoidance task. However, CGS 19755 did not show a unique propensity for learning and memory disruption compared to other anticonvulsants.

Acetylcholine↗