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Biomedical subjects

A R Williams

Publications and source records attributed to A R Williams.

At least 55 records · Page 3Linked to original sources
PubMed1998

Distinct mechanism for antidepressant activity by blockade of central substance P receptors.

The localization of substance P in brain regions that coordinate stress responses and receive convergent monoaminergic innervation suggested that substance P antagonists might have psychotherapeutic properties. Like clinically used antidepressant and anxiolytic drugs, substance P antagonists suppressed isolation-induced vocalizations in guinea pigs. In a placebo-controlled trial in patients with moderate to severe major depression, robust antidepressant effects of the substance P antagonist MK-869 were consistently observed. In preclinical studies, substance P antagonists did not interact with monoamine systems in the manner seen with established antidepressant drugs. These findings suggest that substance P may play an important role in psychiatric disorders.

Adolescent↗
PubMed1998

Sonoporation of erythrocytes by lithotripter shockwaves in vitro.

Sonoporation of red blood cells was examined in relation to cavitation-induced hemolysis. FITC-dextran at 580,000 MW was added to suspensions of canine erythrocytes and the mixture was exposed to lithotripter shockwaves. Exposure at 5% or 50% hematocrit in PBS or 50% in plasma yielded not only hemolysis but also FITC-dextran uptake in surviving cells. Hemolysis increased with increasing numbers of shockwaves. The numbers of cells with fluorescent dextran uptake remained roughly constant for 250-1000 shockwaves, but this represented an increasing percentage of the surviving cells. In addition, fluorescent microspheres formed spontaneously in samples with hemolysis. An air bubble was needed in the chamber to obtain substantial effects, implicating the cavitation mechanism. The exposure-response trends could be modeled by simple theory for random interaction of the cells with bubbles.

Air↗
PubMed1998

The anesthetic management of the pediatric strabismus patient.

Postoperative nausea and vomiting continues to be a common perioperative complication for pediatric strabismus patients. Postoperative pain management and the choice of general anesthetic can increase the incidence of perioperative nausea. Current techniques for induction of general anesthesia and selection of agents, prevention and treatment of postoperative pain, and options for antiemetic therapy will be reviewed.

Anesthesia↗
PubMed1998

Use of intravenous fosfestrol tetrasodium (Honvan) infusion in treatment of symptomatic advanced prostate cancer.

Fosfestrol tetrasodium (Honvan) is a synthetic oestrogen-based compound. Studies have suggested its use in the treatment of localised, advanced and hormone-refractory prostate cancer. This series of 17 patients with advanced disease documents the response, both subjective and objective, to standard dose intravenous Honvan infusion. Infusions were well tolerated, with no cardiovascular side-effects. Twelve patients received Honvan as de novo therapy, of whom 10 (83%) described subjective improvement and 11 (92%) had objective evidence of improvement, 11 (92%) had documented falls in prostate-specific antigen (PSA) levels. Nine patients received Honvan infusions as secondary treatment for hormone-escaped disease (1 patient received Honvan for a second time and another for a second and third time). Of these, 1 (11%) had a documented fall in PSA; 3 (33%) reported a subjective symptomatic improvement, and 2 (22%) demonstrated objective evidence of improvement. Patients with symptoms from bulk abdomino-pelvic disease seemed to fare better than those with bony metastases. This may suggest a specific indication for Honvan in a subgroup of patients with acute obstructive events of the ureters, urethra or circulatory vessles, in particular its value as a de novo therapy. In those patients who received Honvan as secondary therapy, some response was seen in a third, but overall these patients remained hormone-refractory.

Journal Article↗
PubMed1998

Expression of oestrogen receptor alpha and beta in cultured human ovarian surface epithelial cells.

Ovarian surface epithelial (OSE) cells participate in the formation of the ovarian cortex and are potential targets of oestrogen action. Oestrogens typically act through nuclear oestrogen receptors (ER) of which there are two known subtypes: ERalpha and ERbeta. In view of the potential importance of oestrogen as a local regulator of OSE cell function, we screened for ERalpha and ERbeta mRNA in primary OSE cell cultures by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, and used freshly isolated granulosa cells (GC) and granulosa-lutein cells (GLC) as positive controls. OSE cells, scraped from the ovarian surface of women undergoing laparotomy for benign gynaecological conditions, were cultured for up to 21 days to obtain enough cells for mRNA extraction. GC were obtained from spontaneously cyclic women undergoing total hysterectomy; while GLC were obtained from follicular aspirates of gonadotrophin-stimulated in-vitro fertilization patients. Total RNA (1 microg) was reverse transcribed into single-stranded cDNA for PCR (30 cycles) using primers selected to give specific ERalpha and ERbeta products. The ERalpha and ERbeta PCR products, authenticated by cloning and sequencing, were both weakly detectable by Southern analysis in cultured OSE cells and readily detectable in GC and GLC. These results show that cultured human OSE express both ERalpha and ERbeta mRNA, consistent with a role for oestrogen in the regulation of OSE cell function in vivo.

Adult↗
PubMed1998

Pharyngeal flap necrosis as a cause of airway obstruction during induction of anesthesia.

Anesthesiologists should approach the airway carefully in the patient with a diagnosis of head and neck carcinoma, particularly if the patient has had previous surgery and reconstruction. Patients with head and neck carcinoma may be difficult intubations due to altered anatomy from the tumor or fibrotic changes because of radiation therapy. Our patient had had pharyngectomy and reconstruction with a pectoralis major skin flap. The patient returned to the operating suite for wide-excision pharyngectomy and had acute airway obstruction after induction of general anesthesia. The pectoralis flap had necrosed, pulling away from the pharyngeal wall and obstructing the patient's glottic opening.

Aged↗
PubMed1998

A double-blind, placebo-controlled evaluation of the effects of RW94 on the body weight of both overweight and obese healthy volunteers.

RW94 is a naturally occurring common inorganic substance and a permitted additive in the food industry which binds to and precipitates free fatty acids in vitro. Our preliminary clinical trial showed a statistically significant increase in the quantity of faecal fat excreted by volunteers who had consumed RW94, showing that the fatty acids were also precipitated and not absorbed in vivo. It is therefore anticipated that RW94 will aid weight loss by preventing the absorption of some of the dietary fat. Five grams of RW94 were administered orally after each main meal to half of a group of 32 overweight or obese, but otherwise healthy, volunteers, the others receiving a placebo of maize starch. There was a statistically significant (p < 0.05) reduction in the mean weights of the RW94 group relative to their controls at three weeks, and this reduction was maintained throughout the remainder of the six-week trial period. In accordance with our previous findings, there was a higher incidence of abdominal discomfort, rumbling stomach and flatulence among the RW94 group, reflecting the possible transient changes in the bacterial ecosystem of the lower gut in response to the increased delivery of nutrients. These adverse events diminished as the bacteria apparently re-established equilibrium. It appears that the incidence of abdominal discomfort in its various forms following consumption of RW94 is lower than that initially indicated in the preliminary study. Thus, this second clinical trial performed under conditions approximating to the 'real life' situation confirmed that RW94 appears to help reduce the increase in weight following the consumption of excessive dietary fat without undue discomfort or inconvenience from adverse sequellae.

Adult↗
PubMed1997

In vitro and in vivo predictors of the anti-emetic activity of tachykinin NK1 receptor antagonists.

The ability of tachykinin NK1 receptor antagonists to inhibit GR73632 (D-Ala-[L-Pro9,Me-Leu8]substance P-(7-11))-induced foot tapping in gerbils was employed as an indirect measure of brain penetration and this was compared with their ability to prevent acute emesis induced by cisplatin in ferrets. (+)-GR203040 ((2S,3S and 2R,3R)-2-methoxy-5-tetrazol-1-yl-benzyl-(2-phenyl-piperidin- 3-yl)-amine), CP-99,994 ((2S,3S)-cis-3-(2-methoxybenzylamino)-2-phenyl piperidine) dihydrochloride), and L-742,694 (2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(5-(3-oxo-1,2, 4-triazolo)methylmorpholine) potently inhibited GR73632-induced foot tapping (ID50 < or = 0.85 mg/kg), and acute retching induced by cisplatin (ID50 < or = 0.18 mg/kg). RPR100893 ((3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(S)-2-(2-m ethoxyphenyl)proprionyl] perhydroisoindol-4-ol) was not a potent antagonist of retching (ID50 4.1 mg/kg) or foot tapping (ID50 > 10 mg/kg). High doses (3-10 mg/kg) of CGP49823 ((2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[(4-quinolinyl)methyl] -4-piperineamine) dihydrochloride), FK888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-L-propyl]-N-methy l-N-phenylmethyl-L-3-(2-naphthyl)-alaninamide), and LY303870 ((R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4-(pi peridinyl)piperidin-1-yl)acetyl)amino]propane) were required to inhibit foot tapping; these agents were not anti-emetic in this dose range. SR140333 ((S)-1-[2-[3-(3,4-dichlorphenyl)-1 (3-isopropoxyphenylacetyl)piperidin-3-yl] ethyl]-4-phenyl-1 azaniabicyclo [2.2.2]octane; 3-10 mg/kg) failed to inhibit foot tapping or emesis. Affinities for the human and ferret tachykinin NK1 receptor were highly correlated (r = 0.93, P = 0.0008). Inhibition of foot tapping in gerbils, but not NK1 receptor binding affinity, predicted anti-emetic activity in ferrets (r = 0.75, P < 0.01). These findings confirm that the anti-emetic activity of tachykinin NK1 receptor antagonists is dependent on brain penetration.

Administration, Oral↗
PubMed1997

Effects of the bradykinin B1 receptor antagonist des-Arg9[Leu8]bradykinin and genetic disruption of the B2 receptor on nociception in rats and mice.

The contributions of B1 and B2 bradykinin receptors to acute and chronic inflammatory hyperalgesia were examined using the peptide B1 receptor antagonist des-Arg9[Leu8]bradykinin and transgenic Bk2r-/- mice. In normal rats and mice, des-Arg9[Leu8]bradykinin (30 nmol/kg i.v. or s.c.) inhibited carrageenan-induced hyperalgesia and the late phase nociceptive response to formalin. The active dose range was narrow, suggesting partial agonist activity of this peptide. In rats with monoarthritis, des-Arg9[Leu8]bradykinin (up to 30 nmol/kg i.v.) failed to reduce the number of vocalisations elicited by gentle flexion and extension of the inflamed limb; however, hyperalgesia was exacerbated by administration of the B1 receptor agonist des-[Arg9]bradykinin (100 nmol/kg i.v.), consistent with other evidence for local induction of B1 receptors during adjuvant-induced arthritis. The nociceptive response to intraplantar injection of bradykinin (10 nmol) and hyperalgesia induced by carrageenan (0.6 mg) were absent in Bk2r-/- mice, indicating that stimulation of B2 receptors is an essential step in the initiation of some nociceptive and inflammatory reactions. However, the nociceptive response to formalin (2.5% intraplantar), including inhibition of the late phase by des-Arg9[Leu8]bradykinin (0.3 nmol), and induction of thermal hyperalgesia by Freund's adjuvant (0.1%) appeared intact in Bk2r-/- mice. These findings support other evidence for an involvement of B1 receptors in inflammatory hyperalgesia and suggest that B1 receptor antagonists may be clinically useful as anti-inflammatory and analgesic drugs.

Animals↗
PubMed1997

Electrothermal branding for embryo labeling.

A novel embryo labeling technique based on electrothermal branding is developed. Two types of micro branding irons are fabricated and tested. One utilizes 25 microns tungsten wire as the heating element. The other utilizes surface micromachining techniques to fabricate polysilicon branding irons. The thermal behavior of the branding irons and the heat distributions in the embryos are analytically modeled. Micron-scale labels on unfertilized bovine embryos are achieved.

Animal Identification Systems↗
PubMed1997

Continuous transdermal oestrogen and interrupted progestogen as a novel bleed-free regimen of hormone replacement therapy for postmenopausal women.

OBJECTIVE: To investigate the effects of a hormone replacement therapy regime of continuous oestrogen and interrupted progestogen, administered transdermally, on the endometrium of postmenopausal women, the pattern of bleeding and relief of menopausal symptoms. DESIGN: Volunteer pilot study of up to six months duration involving weekly application of an oestrogen-only skin patch releasing 50 microg oestradiol per day interspersed with a combined oestrogen and progestogen patch releasing 50 microg oestradiol and 250 microg norethisterone acetate per day for three days. Transvaginal ultrasound measurements of endometrial thickness and endometrial biopsies were performed in the third month of treatment at the end of both an oestrogen-only phase of treatment and a combined oestrogen-progestogen phase. SETTING: Specialist community menopause clinic, Dean Terrace Centre, Edinburgh. PARTICIPANTS: Fifteen healthy postmenopausal women. MAIN OUTCOME MEASURES: Effect of treatment on endometrial histology, the immunolocalisation of oestrogen and progesterone receptors and the cell proliferation marker Ki 67 after three months of treatment and the proportion of women without bleeding at six months. RESULTS: Treatment provided relief of hot flushes and by the sixth month of study 10 of the 14 women who completed treatment had no vaginal bleeding (71%). No endometrial hyperplasia or atypical changes were observed in biopsies and ultrasound measurements of endometrial thickness demonstrated a thin endometrium. Reduced immunostaining for Ki 67 was observed in endometrium from the combined phase of treatment compared with the oestrogen-only phase, consistent with a progestogenic-antagonism of proliferation. Exposure to progestogen did not suppress steroid receptors as similar immunostaining was observed in both treatment phases. CONCLUSIONS: Continuous oestrogen and interrupted progestogen administered transdermally offers promise as a novel bleed-free hormone replacement therapy for postmenopausal women.

Administration, Cutaneous↗
PubMed1996

The effect of ultrasound on Escherichia coli viability.

The effect of continuous-wave ultrasound on the viability of Escherichia coli HB101 was assessed using a 20 kHz ultrasonic processor. A standardised cell suspension of fixed concentration was used to investigate the influence of different physical and environmental conditions on ultrasound susceptibility. Cell viability decreased exponentially with time at different intensities of ultrasound. Increasing intensity caused a decrease in decimal reduction times. Loss of cell viability occurred primarily from the mechanical effects of ultrasound rather than free radical damage. E. coli susceptibility was also shown to vary with growth conditions, whereby cells cultivated either on agar or harvested from the stationary phase of liquid culture were significantly more susceptible to ultrasound than an equivalent population obtained from the exponential phase of liquid growth. The implication of these results is discussed in relation to the use of ultrasound as a novel means of bacterial transformation.

Escherichia coli↗
PubMed1996

The prognostic value of epidermal growth factor receptor mRNA expression in primary ovarian cancer.

The expression of mRNA for the epidermal growth factor (EGF) receptor, EGF and transforming growth factor alpha (TGF-alpha) was determined in 76 malignant, six borderline and 15 benign primary ovarian tumours using the reverse transcriptase-polymerase chain reaction and related to clinical and pathological parameters. Of the malignant tumours, 70% (53/76) expressed EGF receptor mRNA, 31% (23/75) expressed EGF mRNA and 35% (26/75) expressed TGF-alpha mRNA. For the borderline tumours, four of six (67%) expressed EGF receptor mRNA, 1/6 (17%) expressed TGF-alpha mRNA and none expressed EGF mRNA. Finally, 33% (5/15) of the benign tumours expressed EGF receptor mRNA, whereas 40% (6/15) expressed EGF mRNA and 7% (1/15) expressed TGF-alpha mRNA. The presence of the EGF receptor in malignant tumours was associated with that of TGF-alpha (P = 0.0015) but not with EGF (P = 1.00), whereas there was no relationship between the presence of EGF and TGF-alpha (P = 1.00). EGF receptor mRNA expression was significantly and positively associated with serous histology (P = 0.006) but not with stage or grade. Neither EGF nor TGF-alpha showed any link with histological subtype or stage. The survival of patients with malignant tumours possessing EGF receptor mRNA was significantly reduced compared with that of patients whose tumours were negative (P = 0.030 for all malignant tumours; P = 0.007 for malignant epithelial tumours only). In contrast, neither the expression of TGF-alpha nor EGF was related to survival. These data suggest that the presence of EGF receptor mRNA is associated with poor prognosis in primary ovarian cancer.

Base Sequence↗
PubMed1996

Trends in-original research published from the United Kingdom in the antimicrobial chemotherapy literature, 1980-1994.

There is a feeling that the contribution of researchers from the United Kingdom in the antimicrobial chemotherapy area is in decline, and we, therefore, reviewed publications in the Journal of Antimicrobial Chemotherapy (JAC) and Antimicrobial Agents and Chemotherapy (AAC) in 4 of the last 14 years. In absolute numbers the total number of UK first author publications in these two journals were 103, 78, 107 and 82 in 1980, 1985, 1990 and 1994 respectively. The percentage of first author papers from the UK in JAC was 35%, 21%, 24%, 23% and in AAC was 5.7%, 4.9%, 5.1% and 4.7% for the years 1980, 1985, 1990 and 1994 respectively. Within the UK there has been a relative decline in the number of publications produced by NHS hospital departments and an increase in those produced by universities. Ten institutions (four universities, two pharmaceutical companies and four NHS departments) produced almost half of the UK publications. There is no room for complacency about the state of British antimicrobial research and the relative decline in the NHS hospital sector's contribution, the largest contributor numerically, even before the full impact of the ongoing NHS reforms, is cause for concern.

Anti-Infective Agents↗
PubMed1996

Effects of daily low dose mifepristone on endometrial maturation and proliferation.

Following an ovulatory control cycle, six women took 2 mg of mifepristone daily for 30 days. Endometrial biopsies were collected in the control cycle between 7 and 11 days after the plasma luteinizing hormone (LH) surge and on the corresponding day of the treatment cycle (days 19-28). In order to investigate the effects of unopposed oestrogen on the endometrium, persistent proliferative endometrium was obtained from six women with anovulatory infertility due to polycystic ovarian syndrome (PCOS) on a similar cycle day (days 21-23) following a progestogen-induced withdrawal bleed. Endometrium was evaluated for histology and immunolocalization of oestrogen receptors (ER), progesterone receptors (PR) and the cell proliferation markers [proliferating cell nuclear antigen (PCNA) and Ki67]. Treatment with mifepristone inhibited ovulation in four of the six subjects. In the two subjects in whom ovulation did occur, secretory transformation was delayed, suggesting that successful implantation of a blastocyst would be unlikely. In subjects who remained anovulatory during treatment, the histology and pattern of steroid receptor expression was similar to proliferative phase endometrium. In women with PCOS, mitoses and intense immunostaining for ER, PR and cell proliferation markers were observed in both glands and stroma. Although PCNA and Ki67 immunostaining were also present in mifepristone-treated endometrium from subjects who did not ovulate, there were no mitoses and significantly less ER immunostaining in spite of exposure to unopposed oestrogen for a similar duration. Since PCNA and Ki67 detect cells throughout all stages of the cell cycle this would suggest that mifepristone might affect the entry of cells into the mitotic phase of the cell cycle and, therefore, might prevent endometrial hyperplasia. These findings add further evidence to support the contraceptive potential and antiproliferative activity of daily low dose mifepristone.

Adult↗