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Biomedical subjects

M Williams

Publications and source records attributed to M Williams.

At least 523 records · Page 29Linked to original sources
PubMed1989

Identification of the A2 adenosine receptor binding subunit by photoaffinity crosslinking.

A high-affinity iodinated agonist radioligand for the A2 adenosine receptor has been synthesized to facilitate studies of the A2 adenosine receptor binding subunit. The radioligand 125I-labeled PAPA-APEC (125I-labeled 2-[4-(2-[2-[(4- aminophenyl)methylcarbonylamino]ethylaminocarbonyl]- ethyl)phenyl]ethylamino-5'-N-ethylcarboxamidoadenosine) was synthesized and found to bind to the A2 adenosine receptor in bovine striatal membranes with high affinity (Kd = 1.5 nM) and A2 receptor selectivity. Competitive binding studies reveal the appropriate A2 receptor pharmacologic potency order with 5'-N-ethylcarboxamidoadenosine (NECA) greater than (-)-N6-[(R)-1-methyl- 2-phenylethyl]adenosine (R-PIA) greater than (+)-N6-[(S)-1-methyl-2- phenylethyl]adenosine (S-PIA). Adenylate cyclase assays, in human platelet membranes, demonstrate a dose-dependent stimulation of cAMP production. PAPA-APEC (1 microM) produces a 43% increase in cAMP production, which is essentially the same degree of increase produced by 5'-N- ethylcarboxamidoadenosine (the prototypic A2 receptor agonist). These findings combined with the observed guanine nucleotide-mediated decrease in binding suggest that PAPA-APEC is a full A2 agonist. The A2 receptor binding subunit was identified by photoaffinity-crosslinking studies using 125I-labeled PAPA-APEC and the heterobifunctional crosslinking agent N-succinimidyl 6-(4'-azido-2'-nitrophenylamino)hexanoate (SANPAH). After covalent incorporation, a single specifically radiolabeled protein with an apparent molecular mass of 45 kDa was observed on NaDodSO4/PAGE/autoradiography. Incorporation of 125I-labeled PAPA-APEC into this polypeptide is blocked by agonists and antagonists with the expected potency for A2 receptors (see above) and is decreased in the presence of 10(-4) M guanosine 5'-[beta, gamma-imido]triphosphate. Photoaffinity crosslinking of the A1 adenosine receptor binding subunit with 125I-labeled 8-[4-[2-(4- aminophenylacetylamino)ethyl]carbonylmethyloxyphenyl]-1,3-di propylxanthine (PAPAXAC) (an A1 selective photoaffinity probe) in the same tissue reveals a 38-kDa peptide that exhibits the appropriate A1 receptor pharmacology. 125I-labeled PAPA-APEC, therefore, has identified the A2 receptor binding subunit as a 45-kDa protein that is unique and distinct from the A1 binding subunit.

Adenosine↗
PubMed1989

Cyclosporin A in the treatment of childhood glomerulonephritis.

Seven children with steroid resistant nephrotic syndrome (focal segmental sclerosis in six, mesangial proliferation in one) were treated with Cyclosporin A for 12 weeks. Five of these children were also resistant to cyclophosphamide. All patients had normal renal function. Cyclosporin was started at 8 mg/kg/day then increased until a trough blood level of 100-300 ng/ml (HPLC) was achieved. Three of the seven patients achieved complete remission, and the other four had a significant reduction in their proteinuria (p less than 0.05). In the three patients who achieved complete remission, relapse of proteinuria occurred within six weeks of ceasing Cyclosporin. All patients experienced some impairment in renal function with mean creatinine clearance decreasing from 129 +/- 19 to 91 +/- 13 ml/min/1.73m2 (p less than 0.05). One child was subsequently treated with Cyclosporin for 12 months. He remains in remission with a repeat renal biopsy showing no evidence of nephrotoxicity. One other child with steroid sensitive minimal change nephrotic syndrome who had severe steroid toxicity was treated with a lower dose (5 mg/kg/day) for 12 months. She remained in remission off steroids, but relapsed 16 weeks after Cyclosporin was ceased. A renal biopsy after 12 months showed no nephrotoxicity. Cyclosporin should be considered in steroid resistant nephrotic syndrome, and in children with minimal change disease who show signs of steroid toxicity and short remission period after cyclophosphamide. Serial renal biopsies are recommended with prolonged therapy.

Child↗
PubMed1989

Simple nontoxic treatment of advanced metastatic seminoma with carboplatin.

Between 1982 and 1986, 34 patients with advanced metastatic seminoma were treated with four to six courses of single-agent carboplatin administered at 400 mg/m2 every 4 weeks either on an outpatient basis or during 24-hour admissions. Patients with raised serum alphafetoprotein (AFP) or with multiple (more than three) lung metastases were excluded since these features may indicate a nonseminomatous component. In this series 20 patients were previously untreated except for orchiectomy, and 14 patients had received prior radiotherapy restricted to infradiaphragmatic nodal areas. Treatment was extremely well tolerated. No patient suffered renal damage, neurotoxicity, or ototoxicity, and there were no episodes of neutropenic septicemia, thrombocytopenic hemorrhage, or bruising. The actuarial 2-year survival was 94% (95% confidence intervals, 83% to 100%) with follow-up of 12 to 46 months from completion of carboplatin (mean, 26 months). The actuarial chance of remaining alive and free from progressive disease at 2 years was 80% (95% confidence intervals, 66% to 94%). Of six patients who relapsed, five are currently in remission 9 to 18 months after completion of salvage treatment. This level of antitumor activity is equivalent to that seen with aggressive combination regimens. Single-agent carboplatin should be considered the treatment of choice for advanced stages of malignant seminoma when limitation of toxicity is considered important; however, the rarity, especially of extranodal metastases from seminoma, leads to the need for further investigation using this approach.

Adult↗
PubMed1989

Measurement of respiratory morbidity in general practice in the United Kingdom during the acid transport event of January 1985.

The Weekly Returns System of the Royal College of General Practitioners was used to assess the effect on respiratory illness of the acid transport event that occurred during January 1985. The pollution event, as assessed by SO2 and smoke levels measured at pollution monitoring stations within and without the affected area showed only modest rises in SO2 levels, which were less than levels that occurred 4 years earlier. January is the peak time of year for reporting of acute respiratory episodes, and the minor increase in pollution was not reflected in any rise in respiratory morbidity, both for all ages and for different age bands. There was a rise in rates for children up to the age of 14, but this was seen each year and in both polluted and nonpolluted areas. This was probably due to children returning to school after the winter vacation and the subsequent spread of viral infections. The limitations of the two data sets in this analysis are discussed, including the relative insensitivity of weekly data in picking out a short-lived event, the distribution of the practices and pollution monitoring stations, and the effect of the extreme cold weather and the coal miners' strike on domestic coal burning during this event.

Acid Rain↗
PubMed1989

Promoting safety belt use with traffic signs and prompters.

Two studies were conducted examining the stimulus-control effects of conventional traffic signs as prompts for motor vehicle driver safety belt use. Following pilot research which suggested that a traffic sign reading "Fasten Safety Belt" posted at a parking lot exit was effective in producing small increases in safety belt use, Study I demonstrated the superiority of having human prompters display such signs compared to simply posting the signs. Study II replicated the findings of Study I and found that posted signs became more effective in prompting safety belt use if simple posting was preceded by a period involving human prompters who displayed the signs. The results bear upon the development of more effective use of traffic signs in promoting safety belt use and in viewing such use as an instance of rule-governed behavior.

Accidents, Traffic↗
PubMed1989

Jaw movement and bone-conduction in normal listeners and a unilateral hemi-mandibulectomee.

Relative movement between the mandible and skull may compress the auditory meatus and produce an excess sound in the ear canal. To test this, measurements of sound pressure in the ear canal, and movement of the upper and lower jaw are reported on normal subjects and a unilateral hemi-mandibulectomee. On the side the unilateral hemi-mandibulectomee has a jaw and in the subjects with normal jaws, the data confirm that mandible-movement relative to the skull produces sound in the ear canal. The excess sound in the ear canal when the jaw is free to move independently of the skull can be predicted from the relative movement between them.

Bone Conduction↗
PubMed1989

CGS 20625, a novel pyrazolopyridine anxiolytic.

CGS 20625 (2-(4-methoxyphenyl)2,3,5,6,7,8,9,10-octa hydrocyclohepta[b]pyrazolo-[3,4-d]pyridin-3-one) is a potent and selective ligand for the central benzodiazepine receptor (IC50 = 1.3 nM), with little or no affinity to several other neurotransmitter receptor binding sites in vitro. CGS 20625 had a gamma-aminobutyric acid ratio of 0.9 and increased t-[35S]butylbicyclophosphorothionate binding by 20% in vitro, a profile indicative of a partial agonist or mixed agonist/antagonist. In vivo, CGS 20625 blocked a pentylenetetrazol discriminative cue with an ED50 = 1.7 mg/kg p.o. The compound selectively increased conflict responding in the Cook-Davidson paradigm with a minimal effective dose of 0.3 mg/kg p.o., as compared with 3.0 mg/kg p.o. for diazepam. At doses as high as 100 mg/kg p.o., CGS 20625 had no effect on variable interval responding, suggesting minimal sedation. Unlike diazepam, CGS 20625 had no effect on rotorod performance at doses up to 100 mg/kg p.o. indicating no overt muscle relaxation, and did not potentiate the action of ethanol in this behavioral paradigm. Also, CGS 20625 had no marked effect on locomotor behavior, did not potentiate hexobarbital sleep time and had no sedative activity at doses up to 300 mg/kg p.o. CGS 20625 was efficacious in preventing pentylenetetrazol-induced seizures (ED50 = 0.7 mg/kg p.o.), had less efficacy with no clear dose-response relationship against picrotoxin-induced seizures and had no effect on either strychnine or electroshock-induced convulsions at doses up to 300 mg/kg p.o.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

[3H]CGS 21680, a selective A2 adenosine receptor agonist directly labels A2 receptors in rat brain.

Characterization of the adenosine A2 receptor has been limited due to the lack of available ligands which have high affinity and selectivity for this adenosine receptor subtype. In the present study, the binding of a highly A2-selective agonist radioligand, [3H]CGS 21680 (2-[p-(2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamido adenosine) is described. [3H]CGS 21680 specific binding to rat striatal membranes was saturable, reversible and dependent upon protein concentration. Saturation studies revealed that [3H]CGS 21680 bound with high affinity (Kd = 15.5 nM) and limited capacity (apparent Bmax = 375 fmol/mg of protein) to a single class of recognition sites. Estimates of ligand affinity (16 nM) determined from association and dissociation kinetic experiments were in close agreement with the results from the saturation studies. [3H]CGS 21680 binding was greatest in striatal membranes with negligible specific binding obtained in rat cortical membranes. Adenosine agonists ligands competed for the binding of 5 nM [3H]CGS 21680 to striatal membranes with the following order of activity; CGS 21680 = 5'-N-ethylcarboxamidoadenosine greater than 2-phenylaminoadenosine (CV-1808) = 5'-N-methylcarboxamidoadenosine = 2-chloroadenosine greater than R-phenylisopropyladenosine greater than N6-cyclohexyladenosine greater than N6cyclopentyltheophylline greater than S-phenylisopropyladenosine. The nonxanthine adenosine antagonist, CGS 15943A, was the most active compound in inhibiting the binding of [3H]CGS 21680. Other adenosine antagonists inhibited binding in the following order; xanthine amine congener = (1,3-dipropyl-8-(2-amino-4-chloro)phenylxanthine greater than 1,3-dipropyl-8-cyclopentylxanthine greater than 1,3-diethyl-8-phenylxanthine greater than 8-phenyltheophylline greater than 8-cyclopentyltheophylline = xanthine carboxylic acid congener greater than 8-parasulfophenyltheophylline greater than theophylline greater than caffeine. The pharmacological profile of both adenosine agonist and antagonist compounds to compete for the binding of [3H]CGS 21680 was consistent with a selective interaction at the high affinity adenosine A2 receptor. A high positive correlation (r = 0.98, P less than .01) was observed between the pharmacological profile of adenosine ligands to inhibit the binding of [3H]CGS 21680 and the selective binding of [3H]NECA (+50 nM CPA) to high affinity A2 receptors. However, some differences between these assays were found for compounds which have moderate affinity and nonselective actions at both the A1 and A2 adenosine receptor subtypes. Unlike data obtained with nonselective adenosine ligands, the present results indicate that [3H]CGS 21680 directly labels the high affinity A2 receptor in rat brain without the need to block binding activity at the A1 receptor.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine↗
PubMed1989

Using information about elderly subjects attending government medical clinics to tailor nutrition education services to their needs.

A study of the elderly was carried out in 2 Cornwall County parishes (Hanover and Westmoreland) from June to August, 1987. The health status and general situation of the elderly attending Government Medical Clinics was studied to obtain information to design nutrition education services that met their needs. Four Health Centres (two Type II and two Type III) were selected by stratified random sampling for the study. The results indicated that more elderly women (71%) than men (29%) used the Primary Health Care Services. Obesity was more common among women (29%) than men (0%). More men (30%) were underweight than women (9%). Food stamps appeared to be the most regular source of income for the elderly. Most of the elderly (92%) felt that they were not in good health. Although they generally had 2 to 3 meals per day, their food intake, particularly of fruits and peas, appeared to be inadequate. The results point clearly to a need to strengthen the nutrition education services offered to the elderly attending Government Medical Clinics in Cornwall County, Jamaica.

Aged↗
PubMed1989

CGS 21680C, an A2 selective adenosine receptor agonist with preferential hypotensive activity.

CGS 21680C (2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethyl-carboxamido adenosine) a 2-substituted analog of the riboside uronamide, 5'-N-ethylcarboxamido adenosine and the related analog CGS 21577 (2-phenethylamino-5'-N-ethylcarboxamido adenosine), have high in vitro affinity for brain striatal adenosine A2 receptors (IC50 values = 22 and 13 nM, respectively). Both compounds were considerably less active at A1 receptors with CGS 21577 and CGS 21680C having respective IC50 values of 0.76 and 3.1 microM. The former compound was thus 59-fold selective for A2 receptors whereas CGS 21680C was 140-fold selective. In contrast, the reference A2 selective ligand, CV 1808 (2-phenylaminoadenosine), showed only 8-fold selectivity as an A2 ligand, having an IC50 of 115 nM in the [3H]-5'N-ethylcarboxamide adenosine assay and an IC50 of 910 nM at the N6-[3H] cyclohexyladenosine site. Further examination of CGS 21680C showed that the compound was without effect on binding to 17 other putative neurotransmitter/neuromodulator sites indicating its selectivity as an adenosine receptor ligand. In an isolated perfused working rat heart model, CGS 21680C effectively increased coronary flow with an ED25 value of 1.8 nM. The corresponding value for CGS 21577 was 3 nM whereas that for CV 1808 was 110 nM. The EC25 for eliciting bradycardia for all three compounds was greater than 1000 nM. The effects of all three compounds could be reversed by treatment with the xanthine adenosine antagonist, xanthine amine congener.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1988

The NMDA antagonists, CPP and CGS 19755, lack affinity for central benzodiazepine receptors.

CPP (3-(2-carboxypiperazin-4-yl-propyl-1-phosphonic acid), a rigid analog of AP7 (2-amino-7-phosphonoheptanoate), previously shown to be a selective antagonist of the NMDA (N-methyl-D-aspartate) receptor (IC50 = 209 nM) has been reported to be exceptionally active (IC50 = 430 pM) at benzodiazepine binding sites. Re-examination of CPP, and the rigid AP5 analog, CGS 19755 (cis-4-phosphonomethyl-2-piperidine carboxylic acid; 0.001-10,000 nM), showed that, as previously reported, neither compound affected the binding of [3H]flunitrazepam. These compounds are thus selective NMDA receptor antagonists.

Animals↗
PubMed1988

The impact of hydronephrosis on renal function in patients treated with cisplatin-based chemotherapy for metastatic nonseminomatous germ cell tumors.

We analysed renal function before and after chemotherapy in 130 patients with large (greater than 5 cm in diameter) abdominal masses from malignant non-seminomatous germ cell tumors (NSGCT). The mean glomerular filtration rate assessed by 51Chromium (51Cr) ethylenediamine tetraacetic acid (EDTA) clearance was lower in 46 patients with radiologic evidence of hydronephrosis than in 84 patients with abdominal masses but no hydronephrosis (102 ml/min versus 139 ml/min; P less than 0.01). Patients with hydronephrosis who were treated with cisplatin-based chemotherapy demonstrated a slight early improvement in renal function followed by a fall, in contrast to those treated with carboplatin-based chemotherapy in whom renal function improved. Patients with hydronephrosis who showed no improvement in glomerular filtration rate after the first course of chemotherapy were at an increased risk of renal atrophy and chronic renal damage developing. Long-term renal toxicity may be avoided in these patients either by the use of carboplatin or by the use of drainage procedures such as ureteric stenting or nephrostomy.

Adolescent↗
PubMed1988

The bends.

Explore the source record for details and available documents.

Adult↗
PubMed1988

Barriers and incentives for primary care physicians in cancer prevention and detection.

The American Cancer Society estimates that nearly a million new cases of cancer will occur and that approximately a half million lives will be lost in 1987. These figures may double by the year 2000 primarily because of our aging population, with age being the leading risk factor for cancer. It is believed that the majority of cancer can either be prevented or treated successfully if it is diagnosed early. Primary care physicians and other health professionals delivering information on prevention and performing early diagnostic studies in various ambulatory settings represent the key to the reduced morbidity and mortality of cancer by virtue of their position in the health care delivery system within communities. Barriers and incentives for delivering these all important health measures are examined and suggestions are made for their accomplishment. It is recommended that the primary thrust should be toward the development of methodology which will allow the primary care physician to institute these measures in his regular medical practice and to coordinate them with other health maintenance and early diagnostic activities in the ambulatory setting.

Attitude of Health Personnel↗
PubMed1988

Expression of soluble and fully functional ricin A chain in Escherichia coli is temperature-sensitive.

Linkage of ricin A chain (RA) to a cell surface binding antibody or other ligand can result in a potent cytotoxic agent. We expressed the primary sequence for RA in Escherichia coli to facilitate production and to obtain protein free of naturally occurring contaminants, i.e. ricin B chain. Differences in the level of expression and in the characteristics of the expressed protein were noted when several different host/vector systems were tested. Recombinant RA (rRA) was expressed directly under control of the phage lambda major leftward promoter (PL) and the E. coli trp promoter. It was also expressed fused to E. coli alkaline phosphatase sequences, both in the same reading frame for secretion and out-of-reading frame for expression in a cistron-like arrangement. Expression in the PL promoter system, which is temperature-regulated, was achieved at 37 degrees C as well as at 42 degrees C. The protein expressed at these different temperatures had grossly different properties. Whereas rRA expressed at 37 degrees C was soluble and fully active, that produced at 42 degrees C was aggregated, insoluble, and reduced in activity. Soluble rRA could be converted to the insoluble form by incubation at 42 degrees C in vivo, but not in vitro. Hence, this difference in properties does not simply reflect an inherent thermal instability of the protein. Conditions present in vivo, including the possible association with other proteins, are apparently required for this effect on rRA.

Amino Acid Sequence↗